Tetrahydropyridine derivatives

ABSTRACT

A compound of the formula: ##STR1## wherein n is an integer of from 2 to 6; and p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1; or a pharmaceutically acceptable acid addition salt thereof. This compound has a high affinity and specificity to σ receptors, and is thought to be effective for treatment of some psychoses.

This is a divisional application of Ser. No. 07/903,924 filed Jun. 26,1992, now U.S. Pat. No. 5,243,051, which is a division of Ser. No.07/655,585 filed Feb. 15, 1991, now U.S. Pat. No. 5,149,817.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel tetrahydropyridine derivativeswith psychotropic activities.

2. Prior Art

Antidopamine agents such as haloperidol (U.S. Pat. No. 3,438,991) areused as an antipsychotic agent. Adverse reactions in the extrapyramidaltract such as delayed dyskinesia are caused by them during long-termtherapy. Recently, safer drugs, rimcazole (JP. Pat. Publn. No.55-64,585)and BMY 148021 (GB U.S. Pat. No. 2,155, 925), which show high affinityto σ receptors but low affinity to dopamine receptors, have beendeveloped as psychotropic drugs. On the other hand, the existence of abinding site of dextromethorphan (DM) in the central nervous system hasbeen reported (J. Musacchio, M. Klein and L. J. Santiago, The Journal ofPharmacology and Therapeutics 247 (2), 424 (1988), High AffinityDextromethorphan Binding Sites in Guinea Pig Brain; FurtherCharacterization and Allosteric Interactions). DM, which is one of themost popular antitussives, is thought to be effective for ischemicencephalopathy (F. C. Tortella, M. Pellicano and N. G. Bowery, Trips,10(12), 501 (1989), Dextromethophan and neuromodulation: old drug coughsup new activities). It is also thought that the property of σ receptors,which is labeled with [3H]3PPP adopted in the present invention,resembles that of the DM binding site (J. M. Musacchio, M. Klein and P.D. Cano 11, Life Sciences, 45, 1721 (1989), Dextromethorphan and SigmaLigands: Common Sites but Diverse Effects).

SUMMARY OF THE INVENTION

This invention relates to novel tetrahydropyridine derivatives withpsychotropic activities. Furthermore, these compounds have high affinityand specificity to σ receptors, whereby they are thought to be effectivefor some psychoses such as depression, mania, and acute and chronicschizophrenia, and cerebral ischemic disease.

DETAILED DESCRIPTION

The present invention relates to compounds of the formula: ##STR2##wherein Ar is phenyl or thienyl which may have identically ordifferently one or two substituents selected from the group consistingof lower alkyl, lower alkoxy, halogen, substituted or unsubstitutedphenyl, trifluoromethyl, and hydroxy; n is an integer of from 2 to 6; Ris hydroxy or a group of the formula: ##STR3## wherein R¹ is hydrogen orlower alkyl; R² and R³ each is hydrogen or lower alkyl or taken togetherwith the adjacent nitrogen atom may form a 5- or 6-membered heterocyclicgroup, which may be condensed with a benzene ring, where theheterocyclic group may have identically or differently have 1 to 3substituents selected from the group consisting of lower alkyl, halogen,oxo, pyrimidine, and substituted or unsubstituted phenyl; R⁴ is NH, O,or a single bond; X¹ and X² each is hydrogen, lower alkyl, halogen, orhydroxy; p and q each is an integer of 0 or 1, excluding the case hereis O when q is 1, or a pharmaceutically acceptable acid addition saltthereof.

In this specification, the term "lower alkyl" refers to a straight orbranched chain C₁ , to C₆ alkyl including methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, .tert-pentyl, 2-methylbutyl, n-hexyl, isohexyl andthe like.

The term "lower alkoxy" refers to C₁ to C₆ alkoxy including methoxy,ethoxy, propoxy, butoxy, pentyloxy , hexyloxy and the like.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

"Substituted phenyl" means phenyl substituted by one or moresubstituents, of which examples are hydroxy, lower alkyl, lower alkoxy,and halogen.

The "5- or 6-membered heterocyclic group" may contain one or moreadditional heteroatoms including oxygen, sulfur, and nitrogen atoms, andexamples of the 5- or 6- membered heterocyclic group are isothiazole,pyrazole, pyridine, pyrimidine, imidazole, and isoxazole, preferably,pyrrolidine, piperidine, piperazine, imidazolidine, thiomorpholine,morpholine, pyrazolidine, and the like. The above mentioned heterocyclicgroup may be condensed with a benzene ring at any position. Further theymay have identically or differently 1 to 3 substituents selected fromthe group consisting of lower alkyl, halogen, oxo, pyrimidine, andsubstituted or unsubstituted phenyl.

Pharmaceutically acceptable acid addition salts include mineral acidsalts such as hydrochloride, sulfate, nitrate, and phosphate, andorganic acid salts such as acetate, fumarate, citrate, tartarate,maleate, and oxalate, most preferably hydrochloride, maleate andoxalate.

The compounds of this invention can be prepared by the following method.##STR4##

METHOD A

Step 1

The compound (II) is reacted with the compound of the formula:

    R(CH.sub.2)nY(VI)

wherein R, Y, and n each has the same meaning as defined above in anappropriate organic solvent, if necessary in the presence of a base toprepare the compound (III).

The reaction is performed at a temperature of from 50° to 200° C.,preferably from 85° to 120° C., for 1-15 hours, especially for 5-10hours.

Organic solvents which may be used are alcohols such as methanol andethanol, ethers such as diethylether and tetrahydrofuran,dimethylformamide, acetonitrile and the like, most preferablydimethylformamide.

As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide,potassium carbonate, pyridine, triethylamine, and the like may be used.

Step 2

The compound (III) is subjected to dehydration in an organic solvent inthe presence of the acid to prepare the compound (I a).

The reaction is performed at a temperature of from 0° to 120° C.,preferably at room temperature for 1-96 hours, especially for 3-72hours.

The same organic solvent as mentioned in Step 1 may be used.

The acid includes hydrochloride, acetic acid, trifluoroacetic acid andp-toluenesulfonic acid.

METHOD B

Step 1

The compound (II) is reacted with the compound of the formula:

    Z.sup.1 (CH.sub.2)nY(VII)

wherein Z¹, Y, and n each has the same meaning as defined above in anorganic solvent in the presence of a base to prepare the compound (IV).

The reaction is performed at 10°-150° C., preferably from roomtemperature to 110° C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent and the base as mentioned Method A (step 1) maybe used.

The compound (VII) means phthalimide butylbromide,3-bromo-1-chloropropane and the like.

Step 2

The compound (IV) is reacted with the compound of the formula:

    RH(VIII)

wherein R has the same meaning as defined above in an organic solvent,if necessary in the presence of a base to prepare the compound (III).

The reaction is performed at 80°-200° C., preferably at 100°-130° C.,for 1-24 hours, especially for 2-7 hours.

The same organic solvent and the base as mentioned Step 1 may be used.

Step 3

The compound (III) is subjected to dehydration in the same manner asMethod A (step 2) to prepare the compound (I a). Each condition is thesame as Method A (step 2).

METHOD C

Step 1

The compound (II) is reacted with the compound of the formula:

    HO(CH.sub.2)nY(IX)

wherein Y and n each has the same meaning as defined above, preferablyin the presence of the base to prepare the compound (IV).

The reaction is performed at 50°-200° C., preferably at 120°-150° C.,for 3-20 hours, especially for 5-9 hours.

Step 2

The compound (IV) is reacted with a chloride of a nonmetal element toprepare the compound (V).

The reaction is performed at 0°-100° C., preferably at room temperature,for 1-48 hours, especially for 2-24 hours.

The chloride includes sulfur chloride, thionylchloride, hydrochloride,carbon tetrachloride, and the like.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound(III).

The reaction is performed at 0°-100° C., preferably from roomtemperature to 50° C. for 1-96 hours, preferably for 3-72 hours.

Step 4

The compound (III) is subjected to dehydration in the same manner asMethod A (step 2) to prepare the compound (I a).

METHOD D

Step 1

The compound (II) is reacted with N-protected-β-alanine, in the presenceof a condensing agent such as 1,3-dicyclohexylcarbodiimide, and1-hydroxybenzotriazole in an appropriate organic solvent to prepare thecompound (IV).

The reaction is performed at a temperature of from 10° to 150° C.,preferably from room temperature to 70° C., for 1-20 hours, especiallyfor 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used.

Step 2

The compound (IV) is reacted in an appropriate solvent to remove theamino-protecting group. Then the obtained compound is subjected to areduction reaction in the presence of a reductant.

The former reaction is performed at a temperature of from 10° to 150°C., preferably from room temperature to 70° C., for 1-20 hours,especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used,most preferably trifluoroacetic acid.

The latter reduction reaction is performed in the ordinally method inthe presence of the reductant such as lithium aluminium hydride, hydroiodide, hydrogen sulfide, and sodium iodide at a temperature of from 0°to 100° C., preferably room temperature, for 1 to 7 hours, especiallyfor 2 to 4 hours.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (Ia).

The reaction is performed at a temperature of from 50° to 200° C.,preferably from 100° to 130° C., for 30 minutes to 5 hours, especiallyfor 1-3 hours.

The compound of the present invention can be administered orally orparenterally. For example, the compound of the present invention may beorally administered in the form of tablets, powders, capsules, andgranules, or liquid form such as syrup or elixir, and parenterally inthe form of injection of an aqueous or oily suspension.

These preparations can be prepared in a conventional manner by usingexcipients, binders, lubricants, aqueous or oily solubilizers,emulsifier, suspending agents, and the like. And further additives suchas preservatives and stabilizers can be used.

The dosages may be varied depending upon the administration route, age,weight and condition of the patient, and the kind of disease, but isusually 5-1000 mg/day, preferably 20-200 mg/day through the oral route,and 1-500 mg/day, preferably 5-50 mg/day through the parenteral route ina single or divided doses.

The present invention is illustrated by the following examples andreference examples, which are not to be considered as limiting.

The abbreviations used in the examples and reference examples have thefollowing meanings.

Me: methyl, Et: ethyl, t-Bu: tert-butyl,

iPr: isopropyl, Ph: phenyl, Ts: tosyl

DMF: dimethylformamide, aq.: aqueous

EXAMPLE 1

1-[3-{4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine (Ia-1) ##STR5##

(1) A solution of 3.0 g of 4-hydroxy-4-(3,4-dichlorophenyl)piperidine(II-1) and 2.50 g of 1-{(3-chloropropyl)carbamoyl-2-oxopyrrolidine in 35ml of DMF is stirred at 105°-110° C. for 6 hours in the presence of 2.74g of NaI and 4.22 g of K₂ CO₃ (reaction condition 1). The reactionmixture is poured into ice-water, and the solution is extracted withethyl acetate. The organic layer is washed with water, dried over MgSO₄and concentrated under reduced pressure. The obtained oily substance issubjected to column chromatography with silica gel eluting withmethylene chloride/methanol (15/1-10/1 v/v) to prepare 4.20 g of theobjective compound (III-1) as colorless needles. mp.: 135.5°-137.0° C.

Anal Calcd. (%) for C₁₉ H₂₅ N₃ O₃ Cl₂ : C, 54.90; H, 6.10; N, 10.16; Cl,17.21 Found: C, 55.08; H, 6.08; N, 10.14; Cl, 17.11 IR (CHCl₃): 3600,3320, 1712, 1680, 1545, 1489, 1470 NMR (CDCl₃) δ(200 MHz): 1.682 (dd, J₁=12 Hz, J₂ =2 Hz, 2H); 1.772 (quint, J=7 Hz, 2H); 2.042 (quint, J=8 Hz,2H); 2.062 (s, 1H): 2.191 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.409 (t, J=11Hz, 2H); 2.497 (t, J=7 Hz, 2H); 2.628 (t, J=8 Hz, 2H); 2.837 (dd, J₁ =11Hz, J₂ =2 Hz, 2H); 3.394 (q, J= 6 Hz, 2H); 3.854 (t, J=7 Hz, 2H);7.393,7.401,7.716 (sx3,3H)

(2) A solution of 2.77 g of the compound (III-1) and 1.60 g ofp-toluenesulfonic acid in 300 ml of toluene is refluxed for 48 hours toseparate water as azeotropic mixture of toluene. After removal of thesolvent, the residue is dissolved in ethyl acetate and washed withaq.NaOH and water. The solution is dried over Na₂ SO₄ and concentratedunder reduced pressure. The oily residue is subjected to columnchromatography with silica gel, eluting with ethyl acetate-methylenechloride/methanol (20/1 v/v) to prepare 2.26 g (Yield: 89.3%) of theobjective compound (I a-1) as an oil. The maleate is recrystallized fromi-PrOH to prepare 2.50 g colorless needles. mp. 135.5°-136.5° C.

Anal Calcd. (%) for C₁₉ H₂₃ N₃ O₃ Cl₂. C₄ H₄ O₄ : C, 53.84; H, 5.32; N,8.18; Cl, 13.93 Found: C, 53.91; H, 5.31; N, 8.20; Cl, 13.84 IR (Nujol)cm⁻¹ : 3310, 1713. 1680, 1625, 1580, 1550 (sh), 1518, 1485, 1455 NMR(CDCl₃) δ(200 MHz): 1.829 (quint, J=7 Hz, 2H); 2.039 (quint, J=8 Hz,2H); 2.50˜2.55 (m, 4H); 2.612 (t, J=8 Hz, 2H); 2.714 (t, J=6 Hz, 2H);3.171 (q, J=3.3 Hz, 2H); 3.398 (q, J=7 Hz, 2H); 3.874 (t, J=7 Hz, 2H);6.100 (quint, J=2 Hz, 1H); 7.224 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H); 7.397 (d,J=8 Hz, 1H); 7.463 (d, J=2 Hz, 2H); 8.513 (brs, 1H)

EXAMPLE 2-16

The reaction is performed in the same manner as Example 1 to prepare thecompound (I a). The reaction conditions are shown in table 1 and 2, andphysical constants of the compound (III) are shown in table 3 and thoseof the compound (I a) are shown in table 4.

                                      TABLE I                                     __________________________________________________________________________    (Step 1)                                                                       ##STR6##                                                                          (II)               DMF K.sub.2 CO.sub.3                                                                  NaI reaction                                                                             eluent        g (%)                Ex. No.                                                                            X =  R(CH.sub.2).sub.n Y (VI)                                                                    (ml)                                                                              (g) (g) condition (1)                                                                        condition     compd.               __________________________________________________________________________                                                             No.                   2   CF.sub.3 (p) 2.50 g (II-2)                                                          ##STR7##     25  2.28                                                                              2.29                                                                              105-110 7 hr                                                                         CH.sub.2 Cl.sub.2 /MeOH =                                                                   3.89 (92.2)                                                                   (III-2)                3  n-Pr(p) 2.25 g (II-3)                                                               ##STR8##     20  2.85                                                                              2.31                                                                              105 5 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                   2.98 (74.6)                                                                   (III-3)               4   Et(p) 3.00 g (II-4)                                                                 ##STR9##     30  4.04                                                                              3.28                                                                              105 7 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                   4.10 (75.2)                                                                   (III-4)               5   Ph(p) 4.76 g (II-5)                                                                 ##STR10##    57  5.19                                                                              4.22                                                                              105 24 hr.                                                                           CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-10/1     7.31 (92.3)                                                                   (III-5)               6   t-Bu(p) 6.0 g (II-6)                                                                ##STR11##    60  7.11                                                                              5.78                                                                              105 10 hr.                                                                           CH.sub.2 Cl.sub.2 /MeOH =                                                                   8.36 (81.0)                                                                   (III-6)               7   n-Pr(p)  1.95 g (II-3)                                                              ##STR12##    30  2.46                                                                              2.0 105° C. 9 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1˜10/1                                                                             2.0 (65.0)                                                                    (III-7)               8   t-Bu(p) 1.98 g (II-6)                                                               ##STR13##    20  1.35                                                                              1.10                                                                              100° C. 2.6 hr.                                                               CH.sub.3 Cl.sub.2 /MeOH =                                                     19/1-9/1      0.853 (46.9)                                                                  (III-8)               9   CF.sub.3 (p) 2.33 g (II-2)                                                          ##STR14##    30  2.62                                                                              2.14                                                                              100-105° C. 8.5                                                               CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-10/1     2.46 (65.0)                                                                   (III-9)              10   Ph 930 mg (II-5)                                                                    ##STR15##    11  1.015                                                                             0.825                                                                             105° C. 5 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH/NH.sub.                                               4 OH = 128/16/1-                                                                            0.616 (41.0)                                                                  (III-10)             11   t-Bu(p) 844 mg (II-6)                                                               ##STR16##    11  1.00                                                                              0.813                                                                             100° C. 5.5 hr.                                                               CH.sub.2 Cl.sub.2 /MeOH/NH.sub.                                               4 OH = 128/16/1-64/8/1                                                                      0.830 (57.3)                                                                  (III-11)             12   CF.sub.3 (m) 2.5 g (II-7)                                                           ##STR17##    25  2.76                                                                              2.25                                                                              100-105° C. 5.5                                                               CH.sub.2 Cl.sub.2 /MeOH =                                                                   3.8 (90.2)                                                                    (III-12)             13   CF.sub.3 (p) 527 mg (II-2)                                                          ##STR18##     7  0.59                                                                              --  105° C. 7 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-10/1     0.82 (86.0)                                                                   (III-13)             14   t-Bu(p) 2.03 g (II-6)                                                               ##STR19##    20  2.40                                                                              1.95                                                                              105°  C. 7.5                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-7/1      2.99 (82.8)                                                                   (III-14)             15   Me(p) 1.07 g (II-8)                                                                 ##STR20##    26  1.61                                                                              1.31                                                                              95° C. 7 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                     19/1-9/1      0.477 (24.8)                                                                  (III-15)             16   t-Bu(p) 980 mg (II-6)                                                               ##STR21##    20  1.16                                                                              0.94                                                                              105° C. 6.5 hr.                                                               CH.sub.2 Cl.sub.2 /MeOH =                                                     10/1-5/1      1.69 (92.6)                                                                   (III-16)             __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    (Step 2)                                                                      starting material                                                                      acid  solvent (ml)                                                                         reflux time                                                                             eluenting condition (2)                                                                     product (g)                     __________________________________________________________________________    (III -2) TsOH.H.sub.2 O                                                                      toluene (280)                                                                          48 hr.  ethyl acetate-                                                                              I a-2                           4.24 g   (3.90 g)                                                                            dichloro-        CH.sub.2 Cl.sub.2 /MeOH                                                                     2.26 g                                         ethane (70)                                                    (III -3) CF.sub.3 COOH                                                                       --       10 hr.  toluene/      I a-3                           2.52 g   (25 ml)                ethyl acetate = 1/1                                                                         2.22 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                (III -4) CF.sub.3 COOH                                                                       --       10 hr.  ethyl acetate-                                                                              I a-4                           4.10 g   (35 ml)                CH.sub.2 Cl.sub.2 /MeOH                                                                     3.41 g-20/1                     (III -5) CF.sub.3 COOH                                                                       --       9 hr.   CH.sub.2 Cl.sub.2 /MeOH                                                                     I a-51-20/1                     2.73 g   (30 ml)                              2.40 g                          (III -6) CF.sub.3 COOH                                                                       --       4 hr.   ethyl acetate-                                                                              I a-6                           2.08 g   (25 ml)                CH.sub.2 Cl.sub.2 /MeOH                                                                     1.90 g-20/1                                                                   (95.6)                          (III -7) CF.sub.3 COOH                                                                       --      7.5 hr.  toluene/ethyl-                                                                              I a-7                           2.67 g   (30 ml)                ethyl acetate =                                                                             0.24 g                                                          1/1-ethylacetate                                                                            (59.8)                          (III -8) CF.sub.3 COOH                                                                       --      1.8 hr.  toluene/acetone =                                                                           I a-8                           0.822 g  (2 ml)                 2/1 CH.sub.2 Cl.sub.2 /MeOH                                                                 0.697 g                                                                       (88.8)                          (III -9) CF.sub.3 COOH                                                                       --     24.5 hr.  toluene/ethyl I a-9                           2.27 g   (25 ml)                acetate = 1/1 1.13 g                                                          CH.sub.2 Cl.sub.2 /MeOH                                                                     (52.1)-10/1                     (III -10)                                                                              CF.sub.3 COOH                                                                       --       1 hr.   CH.sub.2 Cl.sub.2 /MeOH                                                                     I a-10*                         0.766 g  (10 ml)                              0.572 g                                                                       (60.5)                          (III -11)                                                                              CF.sub.3 COOH                                                                       --       1 hr.   CH.sub.2 Cl.sub.2 /MeOH                                                                     I a-11*                         0.914 g  (10 ml)                              0.854 g                                                                       (75.4)                          (III -12)                                                                              CF.sub.3 COOH                                                                       --       23 hr.  toluene/      I a-12                          3.42 g   (35 ml)                ethyl acetate = 1/1                                                                         3.15 g                                                          CH.sub.2 Cl.sub.2 /MeOH                                                                     (96.0)                          (III -13)                                                                              CF.sub.3 COOH                                                                       --       72 hr.  toluene/ethyl I a-13                          3.45 g   (45 ml)                acetate = 1/1 2.96 g                                                          CH.sub.2 Cl.sub.2 /MeOH                                                                     (89.4)                          (III -14)                                                                              CF.sub.3 COOH                                                                       --       5 hr.   CH.sub.2 Cl.sub.2 /MeOH                                                                     I a-14                          2.82 g   (35 ml)                              2.62 g                                                                        (97.0)                          (III -15)                                                                              CF.sub.3 COOH                                                                       --       3 hr.   toluene/acetone = 2/1                                                                       I a-15                          0.544 g  (1 ml)       (room temperature)      0.313 g                                                                       (59.6)                          (III -16)                                                                              CF.sub.3 COOH                                                                       --       4 hr.   toluene/ethyl I a-16                          1.50 g   (20 ml)                acetate = 1/1 1.40 g                                                          CH.sub.2 Cl.sub.2 /MeOH                                                                     (97.4)-10/1                     __________________________________________________________________________     *: maleate                                                               

                                      TABLE 3                                     __________________________________________________________________________    Compd.                                                                             mp. (°C.)                                                                       Anal. Calcd. (%)                                                No.  (solvent)                                                                              Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                 __________________________________________________________________________    III -2                                                                             151.5-152.5                                                                            C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 :                                             (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 57.92 (58.10)                                                                        3600, 3310, 1713                                                                      1.712 (d-d, J.sub.1 = 12 Hz, J.sub.2 = 2                                      Hz, 2H); 1.776 (quint J = 7 Hz,                             H, 6.26 (6.34)                                                                          1680, 1605, 1510                                                                      2H); 2.026 (quint, J = 7 Hz, 2H); 2.046                                       (s, 1H); 2.210 (t-d,                                        N, 10.15 (10.16)                                                                        1489    J.sub.1 = 13 Hz, J.sub.2 = 4 Hz, 2H);                                         2.432 (t-d, J.sub.1 = 11 Hz, J.sub.2 = 2                                      Hz,                                                         F, 13.57 (13.79)  2H); 2.490 (t, J = 7 Hz, 2H); 2.601 (t, J                                     = 8 Hz, 2H); 2.838 (d-d,                                                      J.sub.1 = 11 Hz, J.sub.2 = 2 Hz, 2H);                                         7.595 (d, J = 8 Hz, 2H); 7.679 (d,                                            J = 8 Hz, 2H); 8.619 (brs, 1H)                III -3                                                                             96.0-97.0                                                                              C.sub.22 H.sub.33 N.sub.3 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (ethyl-  C, 67.84 (68.18)                                                                        3600, 3320, 1713                                                                      1.634 (sextet, J = 7 Hz, 2H);                                                 1.70˜1.85 (m, 4H); 2.018 (quint,             acetate- H, 8.41 (8.58)                                                                          1680, 1602, 1547                                                                      J = 8 Hz, 2H); 2.185 (t-d, J.sub.1 = 13                                       Hz, J.sub.2 = 4 Hz, 2H); 2.38˜2.64           Et.sub.2 O                                                                             N, 10.74 (10.84)                                                                        1490, 1460                                                                            (m, 8H); 7.160 (d, J = 8 Hz, 2H); 7.343                                       (d, J = 8 Hz, 2H); 8.551                                                      (brs, 1H)                                     III -4                                                                             84.0-85.5          (CHCl.sub.3)                                                                          (CDCl.sub.3)                                                          3600, 3320, 1713                                                                      1.235 (t, J = 8 Hz, 3H); 1.72˜1.83                                      (m, 4H); 2.022 (quint,                                                1680, 1545                                                                            J = 7 Hz, 2H); 2.191 (t-d, J.sub.1 = 13                                       Hz, J.sub.2 = 4 Hz, 2H); 2.4˜2.7                                        (m, 8H); 2.819 (d-d, J.sub.1 = 12 Hz,                                         J.sub.2 = 1 Hz, 2H); 3.375 (q,                                                J = 6 Hz, 2H); 3.848 (t, J = 7 Hz, 2H);                                       7.186 (d, J = 8 Hz, 2H);                                                      7.442 (d, J = 8 Hz, 2H); 8.555 (brs, 1H)      III -5                                                                             155.5-156.5                                                                            C.sub.25 H.sub.31 N.sub.3 O.sub.3.                                                      (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       1/5H.sub.2 O                                                                            3600, 3320, 1713                                                                      1.83˜1.73 (m, 4H); 2.014 (quint, J                                      = 8 Hz, 2H); 2.247 (t-d,                                    C, 70.50 (70.63)                                                                        1682, 1545                                                                            J.sub.1 = 14 Hz, J.sub.2 = 4 Hz, 2H);                                         2.458 (t-d, J.sub.1 = 14 Hz, J.sub.2 =                                        1H,                                                         H, 7.46 (7.82)    2H); 2.507 (t, J = 7 Hz, 2H); 2.595 (t, J                                     = 8 Hz, 2H); 2.853 (d,                                      N, 9.65 (9.88)    J = 11 Hz, 2H); 3.386 (q, J = 6 Hz, 2H);                                      3.846 (t, J = 7 Hz, 2H);                                                      7.25˜7.65 (m, 9H); 8.577 (brs, 1H)      III -6                                                                             149.5-150.5                                                                            C.sub.23 H.sub.35 N.sub.3 O.sub.3                                                       (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 68.48 (68.80)                                                                        3600, 3320, 1713                                                                      1.303 (s, 9H); 1.521 (s, 1H); 1.738 (d-d,                                     J.sub.1 = 11 Hz, J.sub.2 = 3 Hz,                            H, 8.69 (8.79)                                                                          1680, 1543                                                                            2H); 1.793 (quint, J = 8 Hz, 2H); 2.022                                       (quint, J = 7 Hz, 2H);                                      N, 10.39 (10.46)  2.195 (t-d, J.sub.1 = 13 Hz, J.sub.2 = 4                                      Hz, 2H); 2.39˜2.53 (m, 4H); 2.593                                       (t, J = 8 Hz, 2H); 2.823 (d, J = 11 Hz,                                       2H); 3.375 (q, J = 7 Hz,                                                      2H); 3.851 (t, J = 7 Hz, 2H); 7.38, 7.43                                      (ABq, J = 9 Hz, 4H);                                                          8.543 (brs, 1H)                               III -7                                                                             161.0˜162.5                                                                      C.sub.22 H.sub.33 N.sub.2 O.sub.3 Cl.                                                   (Nujol) (CDCL.sub.3)                                       (CH.sub.2 Cl.sub.2 -                                                                   1/3 H.sub.2 O                                                                           3310, 2640, 2560                                                                      0.939 (t, J = 7 Hz, 3H); 1.630 (sextet, J                                     = 7 Hz, 2H); 1.781 (d,                             ethyl-   C, 63.46 (63.68)                                                                        1730, 1680                                                                            J = 12 Hz, 2H); 1.87-2.10 (m, 4H); 2.246                                      (t-d, J.sub.1 = 12 Hz,                             acetate) H, 8.02 (8.18)    J.sub.2 = 3 Hz, 2H); 2.50-2.68 (m, 8H);                                       2.920 (d, J = 12 Hz, 2H);                                   N, 6.83 (6.75)    2.957 (t, J = 7 Hz, 2H); 3.804 (t, J = 7                                      Hz, 2H); 7.156, 7.406                                       F, 7.98 (8.54)    (ABq, J = 8 Hz, 4H)                           III - 8                                                                            207.0-210.0                                                                            C.sub.34 H.sub.23 N.sub.2 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O-                                                       C, 63.73 (71.47)                                                                        3663, 3598, 3345                                                                      1.299 (s, 9H); 1.960 (d, J = 14 Hz, 2H);                                      1.95-2.13 (m, 4H);                                 n-hexane)                                                                              H, 8.09 (8.87)                                                                          2630, 2460, 2410                                                                      2.17-2.35 (m, 2H); 2.606 (t, J = 8 Hz,                                        2H); 2.694 (t-d,                                            N, 7.31 (7.25)                                                                          1740, 1692, 1611                                                                      J.sub.1 = 14 Hz, J.sub.2 = 2 Hz, 2H);                                         2.95- 3.10 (m, 4H); 3.25-3.45 (m,                                     1509, 1471, 1460                                                                      4H); 3.800 (t, J = 7 Hz, 2H); 7.368,                                          7.441 (ABq, J = 8 Hz, 4H)                     III -9                                                                             147.0˜148.0                                                                      C.sub.20 H.sub.25 N.sub.2 O.sub.3 F.sub.3                                               (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 59.79 (59.75)                                                                        3600, 1738, 1693                                                                      1.715 (d-d, J.sub.1 = 14 Hz, J.sub.2 = 2                                      Hz, 2H); 1.878 (s, 1H); 1.898                               H, 6.27 (6.97)                                                                          1620    (quint, J = 8 Hz, 2H); 2.021 (quint, J =                                      8 Hz, 2H); 2.152 (t-d,                                      N, 6.79 (6.37)    J.sub.1 = 14 Hz, J.sub.2 = 4 Hz, 2H);                                         2.451 (t-d, J.sub.1 = 15 Hz,                                F, 14.26 (14.18)  J.sub.2 = 2 Hz, 2H); 2.482 (t, J = 8 Hz,                                      2H); 2.584 (t, J = 8 Hz, 2H);                                                 2.862 (d, J = 15 Hz, 2H); 2.936 (t, J = 7                                     Hz, 2H); 3.794 (t,                                                            J = 7 Hz, 2H) 7.579, 7.627 (ABq, J = 8                                        Hz, 4H)                                       III -10                                                                            225.0˜228.0                                                                      C.sub.25 H.sub.33 N.sub.3 O.sub.2                                                       (Nujol) (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --                                                                  .1/10 H.sub.2 O                                                                         3300, 3055, 3030                                                                      1.775 (quint, J = 7 Hz, 2H); 1.845 (d, J                                      = 14 Hz, 2H); 1.89-1.96                            MeOH--Et.sub.2 O)                                                                      C, 73.25 (73.35)                                                                        2810, 2770, 2670                                                                      (m, 4H); 2.171 (t-d, J.sub.1 = 13 Hz,                                         J.sub.2 = 4 Hz, 2H); 2.52-2.63 (m,                          H, 8.26 (8.18)                                                                          1606, 1528, 1487                                                                      4H); 2.900 (d, J = 12 Hz, 2H); 3.25-3.38                                      (m, 4H); 7.30-7.70 (m,                                      N, 10.21 (10.27)                                                                        1471, 1456, 1448                                                                      9H)                                           III -11                                                                            138.5˜140.5                                                                      C.sub.23 H.sub.37 N.sub.3 O.sub.2.                                                      (Nujol) (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       2/5H.sub.2 O                                                                            3350, 3150, 1631                                                                      1.322 (s, 9H); 1.76-1.94 (m, 8H); 2.262                                       (t-d, J.sub.1 = 14 Hz, J.sub.2 = 4                          C, 70.07 (69.98)                                                                        1542, 1509, 1485                                                                      Hz, 2H); 2.50-2.65 (m, 4H); 2.951 (d, J =                                     11 Hz, 2H); 3.30-3.39                                       H, 9.54 (9.65)                                                                          1460, 1441, 1388                                                                      (m, 4H); 5.738 (brs, 1H); 7.378, 7.418                                        (ABq, J = 8 Hz, 4H)                                         N, 10.66 (10.64)                                                III -12                                                                            113.5˜114.5                                                                      C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 :                                             (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 57.90 (58.10)                                                                        3600, 3320, 1713                                                                      1.715 (d-d, J.sub.1 = 12 Hz, J.sub.2 = 2                                      Hz, 2H); 1.780 (quint J = 7 Hz,                             H, 6.26 (6.34)                                                                          1680, 1545, 1490                                                                      2H); 2.000 ((s, 1H); 2.027 (quint, J = 7                                      Hz, 2H); 2.253 (t-d,                                        N, 10.14 (10.16)                                                                        1385, 1332                                                                            J.sub.1 = 13 Hz, J.sub.2 = 4 Hz, 2H);                                         2.442 (d, J = 12 Hz, 2H); 2.504 (t,                         F, 13.49 (13.79)  J = 7 Hz, 2H); 2.606 (t, J = 8 Hz, 2H);                                       2.854 (d-d, J.sub.1 = 11 Hz,                                                  J.sub.2 = 3 Hz, 2H); 3.394 (quint, J = 7                                      Hz, 2H); 3.850 (t, J = 7 Hz,                                                  2H); 7.474 (d, J = 7 Hz, 1H); 7.492 (t, J                                     = 7 Hz, 1H); 7.746 (d,                                                        J = 7 Hz, 1H); 7.871 (s, 1H); 8.678 (brs.                                     1H)                                           III -13                                                                            oil      --        --      (CDCl.sub.3)                                                                  1.30-1.44 (m, 2H); 1.584 (quint ×                                       2, J = 7 Hz, 4H); 1.747 (d,                                                   J = 12 Hz, 2H); 2.022 (quint, J = 7 Hz,                                       2H); 2.216 (t-d, J.sub.1 = 13                                                 Hz, J.sub.2 = 4 Hz, 2H); 2.41-2.49 (m,                                        4H); 2.600 (t, J = 8 Hz, 2H);                                                 2.773 (d, J = 11 Hz, 2H); 3.292 (q, J = 7                                     Hz, 2H); 3.837 (t,                                                            J = 7 Hz, 2H); 7.598, 7.662 (ABq, J = 9                                       Hz, 4H); 8.428 (brs, 1H)                      III -14                                                                            153.0˜154.0                                                                      C.sub.24 H.sub.37 N.sub.3 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 69.29 (69.36)                                                                        3600, 3280, 1702                                                                      1.319 (s, 9H); 1.623 (s, 1H); 1.71-1.86                                       (m, 8H); 2.190 (t-d, J.sub.1 = 13                           H, 8.93 (8.97)                                                                          (sh), 1697, 1645                                                                      Hz, J.sub.2 = 4 Hz, 2H); 2.39-2.58 (m,                                        6H); 2.824 (d, J = 11 Hz, 2H);                              N, 10.14 (10.11)                                                                        1530, 1480, 1460                                                                      3.375 (q, J = 7 Hz, 2H); 3.75-3.82 (m,                                        2H); 7.463, 7.372 (ABq,                                               1400    J = 9 Hz, 4H); 9.479 (brs, 1H)                III -15                                                                            ˜180                                                                             --        --      (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                                         1.782 (d-d, J.sub.1 = 14 Hz, J.sub.2 = 2                                      Hz, 2H); 1.90-2.12 (m, 6H);                                                   2.275 (t-d, J.sub.1 = 14 Hz, J.sub.2 = 2                                      Hz, 2H); 2.330 (s, 3H); 2.600 (t,                                             J = 8 Hz, 4H); 2.965 (t, J = 7 Hz, 4H);                                       3.810 (t, J = 7 Hz, 2H);                                                      7.163, 7.394 (ABq, J = 8 Hz, 4H)              III -16                                                                            129.0˜130.5                                                                      C.sub.28 H.sub.41 N.sub.3 O.1/3 H.sub.2 O                                               (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 76.08 (76.15)                                                                        3600, 1602, 1580                                                                      1.661 (s, 1H); 1.77-1.94 (m, 4H); 2.285                                       (t-d, J.sub.1 = 13 Hz,                                      H, 9.41 (9.51)                                                                          1505(sh), 1495,                                                                       J.sub.2 = 2 Hz, 2H); 2.460 (t, J = 7 Hz,                                      2H); 2.53-2.65 (m, 6H);                                     N, 9.63 (9.51)                                                                          1470, 1460(sh),                                                                       3.18-3.24 (m, 2H); 6.80-7.48 (m, 9H)                                  1455, 1400, 1380                                      __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Compd.                                                                             Mp. (°C.)                                                                       Anal. Calcd. (%)                                                No.  (solvent)                                                                              Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                 __________________________________________________________________________    I a-2                                                                              187.0-188.5                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3                                               (CHCl.sub.3)                                                                          (CDCl.sub.3 --CD.sub.3 OD = 1/5)                   (oxalate)                                                                              .C.sub.2 H.sub.2 O.sub.4                                                                3290, 2600 (br),                                                                      2.00˜2.20 (m, 4H); 2.620 (t, J = 8                                      Hz, 2H); 2.98˜2.87 (brs, 2H);                (i-PrOH) C, 54.45 (54.43)                                                                        1710, 1685, 1615                                                                      3.292 (t, J = 8 Hz, 2H); 3.451 (t, J = 7                                      Hz, 2H); 3.556 (t,                                          H, 5.38 (5.40)                                                                          1550, 1460                                                                            J = 6 Hz, 2H); 3.819 (t, J = 7 Hz, 2H);                                       3.977 (d, J = 3 Hz, 2H);                                    N, 8.76 (8.66)    6.239 (t, J = 3 Hz, 1H); 7.646 (s, 4H)                      F, 12.26 (11.74)                                                I a-3                                                                              162.0-162.5                                                                            C.sub.26 H.sub.35 N.sub.3 O.sub.6 :                                                     (Nujol) (CDCl.sub.3)                                       (maleate)                                                                              C, 64.23 (64.31)                                                                        3330, 1705 (s),                                                                       0.935 (t, J = 7 Hz, 3H); 1.629 (sextet, J                                     = 7 Hz, 2H); 1.828                                 (i-PrOH) H, 7.23 (7.27)                                                                          1695, 1620, 1575                                                                      (quint, J = 7 Hz, 2H); 2.015 (quint, J =                                      7 Hz, 2H); 2.49˜2.64                                  N, 8.54 (8.65)                                                                          1528    (m, 8H); 2.706 (t, J = 6 Hz, 2H); 3.158                                       (q, J = 3 Hz, 2H); 3.387                                                      (q, J = 7 Hz, 2H); 3.858 (t, J = 7 Hz,                                        2H); 6.032 (quint, J = 2                                                      Hz, 1H); 7.117 (d, J = 8 Hz, 2H); 7.302                                       (d, J = 8 Hz, 2H);                                                            8.486 (brs, 1H)                               I a-4                                                                              86.0-87.0                                                                              C.sub.21 H.sub.29 N.sub.3 O.sub.2                                                       (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (ether)  C, 70.97 (70.95)                                                                        3220, 1713, 1682                                                                      1.227 (t, J = 7 Hz, 3H); 1.824 (quint, J                                      = 7 Hz, 2H); 2.015 (quint,                                  H, 8.11 (8.22)                                                                          1545, 1488, 1460                                                                      J = 7 Hz, 2H); 2.527 (t, J = 8 Hz, 2H);                                       2.561 (brs, 2H); 2.591 (t,                                  N, 11.97 (11.82)  J = 8 Hz, 2H); 2.629 (q, J = 8 Hz, 2H);                                       3.150 (q, J = 3 Hz, 2H);                                                      3.386 (q, J = 7 Hz, 2H); 3.856 (t, J = 7                                      Hz, 2H); 6.017 (quint,                                                        J = 2 Hz, 1H); 7.141 (d, J = 8 Hz, 2H);                                       7.310 (d, J = 8 Hz, 2H);                                                      8.490 (brs, 1H)                               I a-5                                                                              144.0-146.0                                                                            C.sub.25 H.sub.29 N.sub.3 O.sub.2                                                       (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (decom.  C, 74.32 (74.41)                                                                        3320, 1702, 1680                                                                      1.840 (quint, J = 7 Hz, 2H); 2.019                                            (quint, J = 8 Hz, 2H); 2.555                       point)   H, 7.21 (7.24)                                                                          1600, 1545, 1485                                                                      (t, J = 8 Hz, 2H); 2.584 (br, 2H); 2.596                                      (t, J = 8 Hz, 2H); 2.733 (t,                       (ethyl   N, 10.49 (10.41)  J = 6 Hz, 2H); 3.190 (q, J = 3 Hz, 2H);                                       3.398 (q, J = 7 Hz, 2H);                           acetate)                   3.863 (t, J = 7 Hz, 2H); 6.128 (quint, J                                      = 3 Hz, 1H); 7.26˜7.63                                                  (m, 9H); 8.504 (brs, 1H)                      I a-6                                                                              173.0-174.0                                                                            C.sub. 23 H.sub.33 N.sub.3 O.sub.2.                                                     (NUjol) (CDCl.sub.3)(free)                                 (decom.) C.sub.4 H.sub.4 O.sub.4                                                                 3320, 1712, 1690                                                                      1.314 (s, 9H); 1.837 (quint, J = 7 Hz,                                        2H); 2.022 (quint, J = 7 Hz,                       (maleate)                                                                              C, 64.68 (64.91)                                                                        1620, 1580, 1543                                                                      2H); 2.5˜2.6 (m, 6H); 2.717 (t, J =                                     6 Hz, 2H); 3.169 (q,                               (i-PrOH--                                                                              H, 7.48 (7.46)    J = 3 Hz, 2H); 3.387 (q, J = 6 Hz, 2H);                                       6.023 (q, J = 2 Hz, 1H);                           MeOH)    N, 8.38 (8.41)    7.332 (s, 4H); 8.496 (brs, 1H)                I a-7                                                                              190.0-191.0                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.                                              (Nujol) (CDCl.sub.3)                                       (oxalate)                                                                              C.sub.2 H.sub.2 O.sub.4                                                                 2500, 1732, 1725                                                                      0.935 (t, J = 7 Hz, 3H); 1.629 (sextet, J                                     = 8 Hz, 2H); 1.978                                 (MeOH)   C, 64.39 (64.85)                                                                        (sh), 1685, 1610                                                                      (sextet, J = 7 Hz, 2H); 1.989 (sextet, J                                      = 7 Hz, 2H); 2.52-2.60                                      H, 7.27 (7.26)                                                                          (br)    (m, 8H); 2.745 (t, J = 6 Hz, 2H); 2.973                                       (t, J = 7 Hz, 2H); 3.195                                    N, 6.12 (6.30)    (q, J = 3 Hz, 2H); 3.795 (t, J = 7 Hz,                                        2H); 6.022 (quint,                                                            J = 2 Hz, 1H); 7.120, 7.299 (ABq, J = 8                                       Hz, 4H)                                       I a-8                                                                              96.0-97.0                                                                              C.sub.23 H.sub.32 N.sub.2 O.sub.2 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (Et.sub.2 O-n-hexane)                                                                  C, 75.23 (74.96)                                                                        1737, 1692, 1508                                                                      1.317 (s, 9H); 1.962 (sextet, J = 6 Hz,                                       2H); 1.996 (sextet,                                         H, 8.73 (8.75)                                                                          1482, 1459, 1427                                                                      J = 6 Hz, 2H); 2.570 (q, J = 8 Hz, 6H);                                       2.721 (t, J = 5 Hz, 2H);                                    N, 7.65 (7.60)                                                                          1364    2.972 (t, J = 7 Hz, 2H); 3.174 (q, J = 3                                      Hz, 2H); 3.801 (t,                                                            J = 7 Hz, 2H); 6.031 (quint, J = 2 Hz,                                        1H); 7.331 (s, 4H)                            I a-9                                                                              149.5-150.5                                                                            C.sub.20 H.sub.23 N.sub.2 O.sub.2 F.sub.3                                               (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 63.17 (63.15)                                                                        1738, 1692, 1615                                                                      1.964 (sextet, J =  7 Hz, 2H); 2.001                                          (sextet, J = Hz, 2H); 2.538                                 H, 6.09 (6.09)                                                                          1477, 1365, 1325                                                                      (q, J = 8 Hz, 6H); 2.745 (t, J = 6 Hz,                                        2H); 2.980 (t, J = 7 Hz,                                    N, 7.38 (7.36)    2H); 3.207 (q, J = 3 Hz, 2H); 3.803 (t, J                                     = 7 Hz, 2H); 6.160                                          F, 15.06 (14.98)  (quint, J = 3 Hz, 1H); 7.472, 7.565 (ABq,                                     J = 8 Hz, 4H)                                 I a-10                                                                             164.0-166.0                                                                            C.sub.25 H.sub.31 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4                                     (Nujol) (CD.sub.3 OD)                                      (malenate)                                                                             C, 68.89 (68.89)                                                                        3403, 3037, 2330                                                                      1.88-2.05 (m, 4H); 2.951 (brs, 2H);                                           3.20-3.40 (m, 6H); 3.557                           (MeOH--Et.sub.2 O)                                                                     H, 6.97 (6.98)                                                                          1700, 1640, 1578                                                                      (brs, 2H); 3.959 (brs, 2H); 6.220 (s,                                         1H); 6.248 (s, 2H); 7.30-7.70                               N, 8.30 (8.31)                                                                          1537, 1498, 1457                                                                      (m, 9H)                                       I a-11                                                                             138.0-140.0                                                                            C.sub.23 H.sub.35 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4.                                    (Nujol) (CD.sub.3 OD)                                      (malenate)                                                                             1/5 H.sub.2 O                                                                           3522, 3362, 2718                                                                      1.316 (s, 9H); 1.87-2.08 (m, 6H); 2.896                                       (brs, 2H); 3.22-3.36 (m,                           (MeOH--Et.sub.2 O)                                                                     C, 66.16 (66.29)                                                                        2350, 1701, 1630                                                                      8H); 3.526 (brs, 2H); 3.918 (brs, 2H);                                        6.117 (quint, J = 3 Hz, 1H);                                H, 8.21 (8.12)                                                                          1579, 1524, 1498                                                                      6.245 (s, 2H); 7.414 (s, 4H)                                N, 8.82 (8.59)                                                  I a-12                                                                             128.0-129.0                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.                                              (Nujol) (CDCl.sub.3)                                       (malenate)                                                                             C.sub.4 H.sub.4 O.sub.4                                                                 3300, 2300 (br),                                                                      1.831 (quint, J = 7 Hz, 2H); 2.027                                            (quint, J = 8 Hz, 2H);                             (i-PrOH--MeOH)                                                                         C, 56.35 (56.36)                                                                        1710, 1638, 1625                                                                      2.51-2.65 (m, 6H); 2.729 (t, J = 6 Hz,                                        2H); 3.186 (q, J = 3 Hz,                                    H, 5.55 (5.52)                                                                          1570, 1530, 1500                                                                      2H); 3.397 (q, J = 7 Hz, 2H); 3.865 (t, J                                     = 7 Hz, 2H); 6.145                                          N, 8.21 (8.22)                                                                          1460, 1445                                                                            (quint, J = 2 Hz, 1H); 7.41-7.63 (m, 4H);                                     8.517 (brs, 1H)                                             F, 11.07 (11.14)                                                I a-13                                                                             128.0-129.5                                                                            C.sub.22 H.sub.28 N.sub.3 O.sub.2 F.sub.3.                                              (Nujol) (CDCl.sub.3)                                       (oxalate)                                                                              C.sub.2 H.sub. 2 O.sub.4.1/2PrOH                                                        3510, 3310, 1708                                                                      1.35-1.47 (m, 2H); 1.613 (quint ×                                       2, J = 7 Hz, 4H); 2.025                            (MeOH-i-PrOH)                                                                          C, 56.18 (56.35)                                                                        1690, 1680, 1615                                                                      (quint, J = 8 Hz, 2H); 2.44-2.65 (m, 6H);                                     2.716 (t, J = 5 Hz, 2H);                                    H, 6.23 (6.39)                                                                          1537, 1480, 1460                                                                      3.181 (q, J = 3 Hz, 2H); 3.312 (q, J = 6                                      Hz, 2H); 3.862                                              N, 7.70 (7.73)    (t, J = 7 Hz, 2H); 6.157 (quint, J = 2                                        Hz, 1H); 7.472, 7.563 (ABq,                                 F, 10.22 (10.49)  J = 8 Hz, 4H); 8.419 (brs, 1H)                I a-14                                                                             185.0-186.5                                                                            C.sub.24 H.sub.35 N.sub.3 O.sub.2.                                                      (Nujol) (CDCl.sub.3)                                       (malenate)                                                                             C.sub.4 H.sub.4 O.sub.4                                                                 3285, 1695, 1648                                                                      1.312 (s, 9H); 1.77-1.88 (m, 6H);                                             2.49-2.56 (m, 6H); 2.704 (t,                       (MeOH)   C, 65.53 (65.48)                                                                        1620, 1580, 1523                                                                      J = 6 Hz, 2H); 3.160 (q, J = 3 Hz, 2H);                                       3.380 (q, J = 7 Hz, 2H);                                    H, 7.62 (7.65)                                                                          1477, 1460, 1450                                                                      3.75-3.82 (m, 2H); 6.026 (quint, J = 2                                        Hz, 1H); 7.328 (s, 4H); 9.444                               N, 8.24 (8.18)    (brs, 1H)                                     I a-15                                                                             109.5-110.0                                                                            C.sub.20 H.sub.26 N.sub.2 O.sub.2                                                       (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (Et.sub.2 O-n-hexane)                                                                  C, 73.79 (73.59)                                                                        1738, 1692, 1512                                                                      1.939 (quint, J = 7 Hz, 2H); 2.007                                            (quint, J = 7 Hz, 2H); 2.328                                H, 8.08 (8.03)                                                                          1485, 1460, 1430                                                                      (s, 3H); 2.49-2.63 (m, 4H); 2.713 (t, J =                                     5 Hz, 2H); 2.969 (t,                                        N, 8.55 (8.58)                                                                          1367    J = 7 Hz, 2H); 3.153 (q, J = 3 Hz, 2H);                                       3.794 (t, J = 7 Hz, 2H);                                                      6.018 (quint, J = 2 Hz, 1H); 7.115, 7.280                                     (ABq, J = 8 Hz, 4H)                           I a-16                                                                             105.0-106.0                                                                            C.sub.28 H.sub.39 N.sub.3 O.sub.2.                                                      (Nujol) (CDCl.sub.5)                                       (malenate)                                                                             C.sub.4 H.sub.4 O.sub.4                                                                 1710, 1622, 1598                                                                      1.315 (s, 9H); 1.78-1.84 (m, 8H);                                             2.43-2.75 (m, 8H); 3.16-3.25                       (i-PrOH--Et.sub.2 O)                                                                   C, 66.49 (66.54)                                                                        1575, 1495(sh)                                                                        (m, 6H); 6.043 (quint, J = 2 Hz, 1H);                                         6.80-7.34 (m, 9H)                                  210.0-212.5                                                                            H, 7.26 (7.29)                                                                          1480, 1462, 1450                                           (MeOH)   N, 6.59 (6.47)                                                                          1385, 1360                                            __________________________________________________________________________

EXAMPLE 17

1-[4-{4-(4-trifluoromethylphenyl)-1,2,5,6-tetarahydropyridin-1-yl}-butylcarbamoyl]-2-oxopyrrolidine(I a-17) ##STR22##

(1) A solution of 2.00 g of4-hydroxy-4-(4-trifluoromethylphenyl)piperidine (II-2) and 2.42 g ofphthalimido butyl bromide in 20 ml of DMF in the presence of 2.26 g ofK₂ CO₃ is stirred at 105° C. for 6 hours. The reaction mixture is pouredinto ice-water, and the solution is extracted with ethyl acetate. Theorganic layer is washed with water, dried over Na₂ SO₄ and concentratedunder reduced pressure. The obtained residue is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(20/1 v/v). The purified substance is recrystallized from methylenechloride/ether to prepare 3.0 g of the compound (IV-1). mp.139.0°-140.5° C.

Anal Calcd. (%) for C₂₄ H₂₅ N₂ O₃ F₃ : C, 64.23; H, 5.73; N, 6.10; F,12.98 Found: C, 64.57; H, 5.64; N, 6.27; F, 12.77 IR (CHCl₃): 3590,1772, 1713, 1618, 1470, 1440, 1409(sh), 1389 NMR (CDCl₃) (200 MHz) δ:1.52-1.80 (m, 6H); 1.843 (s, 1H); 2.152 (td, J₁ =13 Hz, J₂ =4 Hz, 2H);2.37-2.50 (m, 4H); 2.838 (dd, J₁ =9 Hz, J₂ =2 Hz, 2H); 3.728 (t, J=7 Hz,2H); 7.613, 7.640 (ABq, J=9 Hz, 4H) 7.7-7.9 (m, 4H)

(2) A solution of 2.56 g of the compound (IV-1) and 424 mg of hydrazinehydrate in 25 ml of ethanol is refluxed for 3 hours. After the excessagent is distilled off under reduced pressure, the residue is mixed with1.15 g of 1-phenoxycarbonyl-2-oxopyrrolidine and heated at 105° C. for1.5 hours. The reaction mixture is subjected to column chromatographywith silica gel, eluting with methylene chloride/methanol=20/1-10/1 v/v.The obtained material is recrystallized from methylene chloride-ether toprepare 1.76 g (Yield: 73.5%) of the objective compound (III-17) ascolorless needles. mp. 150.5°-152.0° C.

Anal Calcd. (%) for C₂₁ H₂₈ N₃ O₃ F₃ : C, 58.78; H, 6.51; N, 9.75; F,13.56 Found: C, 59.01; H, 6.60; N, 9.83; F, 13.33 IR (CHCl₃): 3590,3320, 1713, 1680, 1618, 1545, 1489, 1460, 1409, 1385, 1328 NMR (CDCl₃):1.57-1.63 (m, 4H); 1.743 (d, J=12 Hz, 2H); 2.019 (quint, J=7 Hz, 2H);2.189 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.341 (s, 1H); 2.42-2.55 (m, 4H);2.595 (t, J=8 Hz, 2H); 2.862 (dd, J₁ =1O Hz, J₂ =2 Hz, 2H); 3.311 (q,J=6 Hz, 2H); 3.822 (t, J=7 Hz, 2H); 7.591, 7.653 (ABq, J=9 Hz, 4H);8.438 (brs, 1H)

(3) A solution of 1.40 g of the compound (III-17) in 20 ml of trifluoroacetic acid is refluxed for 72 hours. After removal of the excessreagent, the residue is poured into sodium hydroxide, and the solutionis extracted with ethyl acetate. The organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily residue is subjectedto column chromatography with silica gel, eluting with methylenechloride/methanol (20/1 v/v) and recrystallized from i-PrOH-ether toprepare 1.31 g (Yield: 97.7%) of the objective compound (I a-17) asneedles. mp. 136.0°-136.5° C.

Anal Calcd. (%) for C₂₁ H₂₆ N₃ O₂ F₃ : C, 61.87; H, 6.49; N, 10.26; F,13.87 Found: C, 61.60; H, 6.40; N, 10.26; F, 13.92 IR (CHCl₃): 3310,1713, 1680, 1615, 1545, 1487, 1458, 1385 1327 NMR (CDCl₃) (200 MHz) δ:1.55-1.67 (m, 4H); 2.031 (quint, J=8 Hz, 2H); 2.47-2.65 (m, 6H); 2.725(t, J=5 Hz, 2H); 3.190(q, J=3 Hz, 2H): 3.344 (q, J=6 Hz, 2H); 3.857 (t,J=8 Hz, 2H); 6.154 (quint, J=2 Hz, 1H); 7.471, 7.564 (ABq, J=8 Hz, 4H);8,436 (brs, 1H)

EXAMPLE 18

1-[N-propyl-N-[3-{4-(4-t-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]]-2-oxopyrrolidine(I a-18) ##STR23##

(1) A solution of 2.00 g of the compound (II-6) and 1.42 g of3-bromo-1-chloropropane in 30 ml of DHF is stirred in the presence of2.37 g of K₂ CO₃ at room temperature for 3.5 hours. The reaction mixtureis poured into ice-water, and the solution is extracted with ethylacetate. The organic layer is washed with water, dried and concentratedunder reduced pressure to prepare 1.32 g of the compound (IV-2).

(2) A solution of 0.5 g of the compound (IV-2) and 0.44 ml of n-propylin 1 ml of DHF is heated at 105° C. for 2 hours under stirring. Themixture is concentrated, and the residue is poured into aq.NaOH. Thesolution is extracted with methylene chloride, the organic layer isdried over MgSO₄ under reduced pressure. The oily residue is mixed with310 mg of 1-phenoxycarbonyl-2-oxopyrrolidine and reacted at 115° C. for2 hours. The reaction mixture is dissolved into methylene chloride,washed with aq.NaOH and aq.NaCl in order, dried over Na₂ SO₄, andconcentrated under reduced pressure. The oily residue is subjected tocolumn chromatography with silica gel, eluting with methylenechloride/methanol (20/1-10/1 v/v) to prepare 500 mg (Yield: 70.0% ) ofthe compound (III-18) as an oil. IR (CHCl₃): 3595, 1720, 1665, 1605,1517, 1465(sh), 1460, 1425, 1400, 1375 NMR (CDCl₃): 0.889 (t, J=7 Hz,3H); 1.316 (s, 9H); 1.594 (q, J=8 Hz, 2H); 1.74-1.89 (m, 4H); 2.076(quint, J=7 Hz, 2H); 2.207 (t, J=15 Hz, 2H); 2.435 (t, J=8 Hz, 2H);2.48-2.60 (m, 4H); 2.80-2.90 (m, 2H); 3.317 (t, J=4 Hz, 2H); 3.421 (t,J=4 Hz, 2H); 3.712 (t, J=7 Hz, 2H); 7.368, 7.436 (ABq, J=8 Hz, 4H)

(3) A solution of 1.40 g of the compound (III-17) in 15 ml oftrifluoroacetic acid is refluxed for 2.5 hours. The solution isconcentrated, and the residue is poured into aq.NaOH. The solution isextracted with ethyl acetate, and the organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily residue is subjectedto column chromatography with silica gel, eluting with toluene/ethylacetate (1/1 v/v) to prepare 1.07 g (Yield: 80%) of the objectivecompound (I a-18) as an oil. mp. 158.5°-159.5° C. (dec.) Anal Calcd. (%)for C₂₆ H₃₉ N₃ O₂.C₂ H₂ O₄. 1/2H₂ O: : C, 64.38; H, 8.11; N, 8.05 Found:C, 64.10; H, 8.07; N, 8.01 IR (Nujol): 3420, 2720, 2590, 2500, 1715,1692, 1675(sh), 1610(br), 1515, 1460 NMR (CD₃ OD) (200 MHz) δ: 0.894 (t,J=7 Hz, 3H); 1.312 (s, 9H); 1.618 (q, J=7 Hz, 2H); 2.117 (quint, J=7 Hz,4H); 2.458 (t, J=8 Hz, 2H); 2.872 (brs, 2H); 3.28-3.37 (m, 4H);3.49-3.56 (m, 4H); 3.695 (t, J=7 Hz, 2H); 3.932 (brs, 2H); 6.089 (quint,J=2 Hz, 1H); 7.402 (s, 4H)

EXAMPLE 19

1-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine(I a-19) ##STR24##

(1) A mixture of 10.061 g of the compound (II-6) and 5.41 ml of3-chloro-1-propanol is stirred at 140° C. for 6 hours in the presence of12.03 ml of Et₃ N. The reaction mixture is recrystallized from methylenechloride-ether-n-hexane to prepare 9.357 g (Yield: 74.0%) of thecompound (IV-3). mp. 122.5°-123.5° C. Anal Calcd. (%) for C₁₈ H₂₉NO₂.1/10H₂ O: C,73.72; H,9.93; N,4.82 Found: C,73.73; H,10.04; N,4.78 IR(CHCl₃) cm⁻¹ : 3600, 3225, 1509, 1472, 1437, 1424, 1399, 1372 (sh), 1366NMR (CDCl₃) δ: 1.31 (s, 9H); 1.62-1.85 (m, 4H); 2.119 (td, J₁ =13 Hz, J₂=4 Hz, 2H); 2.507 (td, J₁ =12 Hz, J₂ =2 Hz, 2H); 2.707 (t, J=6 Hz, 2H);2.973 (d, J=11 Hz, 2H); 3.829 (t, J=6 Hz, 2H); 7.367, 7.417 (ABq, J=8Hz, 4H)

(2) A mixture of 10.568 g of the compound (IV-3) and 26.4 ml of thionylchloride is stirred at room temperature overnight. Excess reagent isdistilled off under reduced pressure, and the residue is poured intoaq.Na₂ CO₃. The solution is extracted with methylene chloride, and theorganic layer is dried over MgSO₄ and concentrated. The residue issubjected to column chromatography with silica gel, eluting withtoluene/acetone (8/1-6/1 v/v) and recrystallized from n-hexane toprepare 2.167 g (Yield: 20.5%) of the compound (V-1) as colorlesscrystals.

Anal Calcd. (%) for C₁₈ H₂₆ NCl: C, 73.86; H, 9.08; N, 4.96; Cl, 12.35Found: C, 74.07; H, 8.98; N, 4.80; Cl, 12.15 IR (CHl₃): 1640, 1610,1510, 1470, 1390, 1380 NMR (CDCl₃) δ: 1.315 (s, 9H); 2.041 (quint, J=7Hz, 2H); 2.50-2.66 (m, 4H); 2.714 (t, J=5 Hz, 2H); 3.169 (q, J=3 Hz,2H); 3.638 (t, J=7 Hz, 2H); 6.032 (quint, J=3H, 1H); 7.334 (s, 4H)

(3) A mixture of 621 mg of the compound (V-1) and 1.78 ml of pyrrolidineis stirred at room temperature for 72 hours. The excess reagent isdistilled off, and the residue is subjected to column chromatographywith silica gel, eluting with methylene chloride/methanol/ammonia(128/16/1 v/v) to prepare 675 mg of the compound (I a-19) as an oil,which is crystallized as maleate and recrystallized from methanol togive 800 mg (yield: 67.3%) of colorless plates. mp. 190.0°-191.0° C.(dec.)

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O₂.C₄ H₄ O₄ : C, 64.74; H, 7.58; N, 5.11Found: C, 64.50; H, 7.58; N, 5.01 IR (Nujol): 2355, 1711, 1620, 1577,1543, 1479(sh), 1461, 1378 NMR (CD₃ OD) δ: 1.314 (s, 9H); 2.122 (quint,J=3 Hz, 2H); 2.20-2.37 (m, 2H); 2.907 (brs, 2H); 3.30-3.43 (m, 6H);3.567 (t, J=6 Hz, 2H); 3.949 (brs, 2H); 6.129 (brs, 1H); 6.269 (s, 2H);7.416 (s, 4H)

EXAMPLE 20

1-[3-{4-(4-trifluoromethyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine(I a-20) ##STR25##

(1) A mixture of 5.00 g of the compound (II-2) and 2.22 ml of3-chloro-1-propanol is stirred in the presence of 4.27 ml of Et₃ N at140° C. for 8 hours. The mixture is subjected to column chromatographywith silica gel, eluting with methylenechloride/methanol/ammonium=64/8/1-32/6/1 v/v. The obtained purifiedsubstance is recrystallized from ether-n-hexane to prepare 5.155 g(Yield: 75.7%) of the compound (IV-4). mp. 116.0°-116.5° C.

Anal Calcd. (%) for C₁₅ H₂₀ NO₂ F₃ : C, 59.31; H, 6.59; N, 4.69; F,18.70 Found: C, 59.40; H, 6.65; N, 4.62; F, 18.79 IR (Nujol): 3335,3075, 2773, 1617, 1462, 1436, 1407, 1378 NMR (CDCl₃) δ: 1.73-1.83 (m,4H); 2.119 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.494 (td, J₁ =12 Hz, J₂ =3Hz, 2H); 2.716 (t, J=6 Hz, 2H); 3.009 (d-d, J₁ =12 Hz, J₂ =2 Hz, 2H);3.836 (t, J=6 Hz, 2H); 7.612 (s, 4H)

(2) The compound (IV-4) 4.892 g is treated in the same manner as Example19(2) to prepare 3.357 g of the compound (V-2) as an oil.

IR (CHCl₃): 1608, 1453, 1439, 1399, 1368(sh), 1319 NMR (CDCl₃): 2.036(quint, J=7 Hz, 3H); 2.54-2.62 (m, 2H); 2.636 (t, J=7 Hz, 2H); 2.733 (t,J=6 Hz, 2H); 3.192 (q, J=3 Hz, 2H); 3.635 (t, J=7 Hz, 2H); 6.152 (quint,J=2 Hz, 1H); 7.466, 7.562 (ABq, J=8 Hz, 4H)

(3) A mixture of 1.05 g of the compound (V-2) and 1.44 ml of pyrrolidineis stirred at room temperature for 32.5 hours, and the reaction mixtureis treated in the same manner as Example 19 (3) to prepare 1.15 g(Yield: 98.2%) of the objective compound (I a-20) as crystals. Themalehate is recrystallized from methanol to prepare 1.04 g (Yield:98.2%) of colorless needles. mp. 175.0-178.0 (dec.)

Anal. Calcd. (%) for C₁₉ H₂₅ N₂ F₃ O₂.C₄ H₄ O₄ C, 57.92; H, 5.74; N,4.97; F, 10.05 Found: C, 56.84; H, 5.83; N, 4.91; F, 9.99 IR (Nujol):2590, 2360, 2160, 1711, 1620, 1560, 1535(sh), 1483, 1458, 1378, 1359 NMR(CD₃ OD): 2.119 (quint, J=3 Hz, 4H); 2.20-2.37 (m, 2H); 2.92 7 (brs,2H); 3.28-3.50 (m, 8H); 3.566 (t, J=6 Hz, 2H); 3.971 (q, J=2 Hz, 2H);6.266 (s, 4H) 6.295 (brs, 1H); 7.681 (s, 4H)

EXAMPLE 21

1-[3-{4-(4-methylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine(I a-21) ##STR26##

(1) A mixture of 10.20 g of the compound (II-8) and 5.5 ml of3-chloro-1-propanol is stirred in the presence of 11 ml of Et₃ N at 140°C. for 5.5 hours. The reaction mixture is recrystallized from methylenechloride-ether to prepare 8.5 g (Yield: 64.0%) of the compound (IV-5).mp. 110.5°-111.5° C.

Anal Calcd. (%) for C₁₅ H₂₃ NO₂ : C, 72.01; H, 9.25; N, 5.58 Found: C,72.25; H, 9.30; N, 5.62 IR (CHCl₃): 3597, 3220, 1513, 1470, 1452, 1437,1423, 1397 NMR (CDCl₃) δ: 1.67-1.81 (m, 4H); 2.087 (td, J₁ =13 Hz, J₂ =4Hz, 2H): 2.337 (s, 3H); 2.479 (td, J₁ =15 Hz, J₂ =3 Hz, 2H); 2.693 (t,J=6 Hz, 2H); 2.952 (d, J=11 Hz, 2H); 3.828 (t, J=5 Hz, 2H); 7.168, 7.372(ABq, J=8 Hz, 4H)

(2) A solution of 12.82 g of the compound (IV-5) in 38 ml oftrifluoroacetic acid is refluxed for 3.1 hours. The reaction mixture isconcentrated, and the residue is poured into aq.NaHCO₃. The mixture isextracted with ethyl acetate, and the organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily substance is subjectedto column chromatography with silica gel, eluting with methylenechloride/methanol/NH₄ OH (128/16/1 v/v). A mixture of 870 mg of theproduct and 8.01 ml of thionyl chloride is stirred at room temperaturefor 2 hours. The excess reagent is distilled away under reducedpressure. The residue is washed with ether and dried under reducedpressure to give 1.067 g (Yield: 99.2%) of the objective compound (V-3)as a light yellowish powder.

IR (CHCl₃): 1600, 1510, 1460, 1410 NMR (CDCl₃): 2.046 (quint, J=7 Hz,2H); 2.334 (s, 3H); 2.54, 2.64 (m, 2H); 2.629 (t, J=7 Hz, 2H); 2.723 (t,J=5 Hz, 2H); 3.173 (q J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint,J=2 Hz, 1H) 7.123, 7.287 (ABq, J=8 Hz, 4H)

(3) A mixture of 466 mg of the compound (V-3) and 0.78 ml of pyrrolidineis stirred at 50° C. for 3 hours and treated in the same manner asExample 19(3) to give the maleate of the objective compound (I a-21). Itis recrystallized from methanol-iPrOH to prepare 225 mg (Yield: 42.5%)of the compound (I a-21) as needles. mp. 180.0°-181.0° C. (dec.)

Anal Calcd. (%) for C₁₉ H₂₈ N₂.2C₄ H₄ O₄ : C, 62.84; H, 6.99; N, 5.48Found: C, 62.78; H, 7.02; N, 5.42

EXAMPLE 22-29

The compound (V-1), (V-2) and (V-3), each of which were obtained in Step1 of Example 19-21, are reacted with amine (VIII) in the same manner asStep 3 in Example 19-21 to prepare the compound (I a). The reactionconditions and physical constants are shown in table 5 and 6.

                                      TABLE 5                                     __________________________________________________________________________     ##STR27##                                                                    Ex. No.                                                                            starting material                                                                      RH            reaction condition                                                                      purification condition                                                                         product mg             __________________________________________________________________________                                                           (%)                    22   (V-1)    HN(i-Bu).sub.2                                                                              33 hours  CH.sub.2 Cl.sub.2 /MeOH                                                       = 49/1-19/1      Ia-22*.sup.1                0.628 g  3.76 ml       reflux                     685 mg                                                                        (51.1%)                23   (V-2)    HN(i-Bu).sub.2                                                                              32 hours  CH.sub.2 Cl.sub.2 /MeOH                                                                        Ia-23*.sup.1                0.602 g  1.50 g        reflux                     338 mg                                                                        (27.1%)                24   (V-3)    HN(i-Bu).sub.2                                                                              20 hours  CH.sub.2 Cl.sub.2 /MeOH                                                                        Ia-24*.sup.1                0.517 g  1.36 g        reflux                     457 mg                                                                        (38.4%)                25   (V-3) 0.924 g                                                                           ##STR28##    150° C. 8.15 hours                                                               toluene/acetone = 19/1-9/1                                                                     Ia-25*.sup.1  930                                                             mg (54.4%)             26   (V-3) 0.624 g                                                                           ##STR29##    150° C. 4.1 hours                                                                CH.sub.2 Cl.sub.2 /MeOH                                                                        Ia-26*.sup.1  963                                                             mg 66.6%)              27   (V-2) 1.02 g                                                                            ##STR30##    100° C. 25 hours (in                                                             toluene/acetone = 3/11/1                                                                       Ia-27*.sup.1  266                                                             mg (15.3%)             28   (V-2)    H.sub.2 N-i-Bu                                                                              15.6 hours                                                                              CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH                                           = 64/8/1         Ia-28                       0.645 g  1.1 ml        reflux                     461 mg                                                                        (63.8%)                29   (V-1) 0.828 g                                                                           ##STR31##    150° C. 3 hours                                                                  CH.sub.2 Cl.sub.2 /MeOH                                                                        Ia-29*.sup.1  773                                                             mg (70.2%)             __________________________________________________________________________     *.sup.1 separated as maleate                                                  *.sup.2 prepared by the reaction with 492 mg of isoindoline and 162 mg of     60% NaH in 5 ml of DMF at 100° C. for 1 hour.                     

                                      TABLE 6                                     __________________________________________________________________________    Compd.                                                                             mp. (°C.)                                                                       Anal Cald. (%)                                                  No.  Rec. sol. *.sup.1                                                                      Found (%) IR (cm.sup.-1)                                                                        NMR (δ) (2000 MHz)                      __________________________________________________________________________    I a-22                                                                             (maleate)                                                                              C.sub.26 H.sub.44 N.sub.2 O.sub.2.                                                      (Nujol) (CD.sub.3 OD)                                      7.76.5˜178.0                                                                     C.sub.4 H.sub.4 O.sub.4                                                                 2620, 2510, 1690                                                                      1.083 (d, J = 7 Hz, 12H); 1.314 (s, 9H);                                      2.158 (7tet, J = 7 Hz, 2H);                        (MeOH--Et.sub.2 O)                                                                     C, 63.46 (63.68)                                                                        1657, 1618, 1579                                                                      2.20-2.37 (m, 2H); 2.913 (brs, 2H); 3.042                                     (d, J = 7 Hz, 4H);                                 needleshaped                                                                           H, 8.02 (8.18)                                                                          1533, 1488, 1460                                                                      3.25-3.37 (m, 4H); 3.588 (t, J = 6 Hz,                                        2H); 3.974 (s, 2H); 6.131                          crystals N, 6.83 (6.75)                                                                          1409, 1378                                                                            (s, 1H); 6.272 (s, 4H); 7.419 (s, 4H)                       F, 7.98 (8.54)                                                  I a-23                                                                             (maleate)                                                                              C.sub.23 H.sub.35 N.sub.2 F.sub.3 O.sub.2.                                              (Nujol) (CD.sub.3 OD)                                      135.0˜136.5                                                                      C.sub.4 H.sub.4 O.sub.4                                                                 2420, 1707, 1616                                                                      1.071 (d, J = 7 Hz, 12H); 2.05-2.35 (m,                                       4H); 2.90-3.30 (m, 4H);                            (MeOH--Et.sub.2 O)                                                                     C, 59.12 (59.23)                                                                        1572, 1485, 1456                                                                      3.20-3.30 (m, 4H); 3.559 (brs, 2H); 3.972                                     (brs, 2H);                                         needleshaped                                                                           H, 6.76 (6.89)                                                                          1377    J = 7 Hz, 2H) 2.54-2.61 (m, 2H); 2.747                                        (t, J = 5 Hz, 2H);                                 crystals N, 4.35 (4.46)    6.260 (s, 5H); 7.674 (s, 4H)                                F, 9.05 (9.07)                                                  I a-24                                                                             (maleate)                                                                              C.sub.23 H.sub.38 N.sub.2 .                                                             (Nujol) (CDCl.sub.3)                                       140.5˜142.5                                                                      C.sub.4 H.sub.4 O.sub.4                                                                 2710, 2500, 1706                                                                      0.872 (d, J = 7 Hz, 12H); 1.685 (quint, J                                     = 7 Hz, 4H); 2.059                                 (MeOH--Et.sub.2 O)                                                                     C, 64.67 (64.79)                                                                        1572, 1480, 1455                                                                      (d, J = 7 Hz, 4H); 2.329 (s, 3H);                                             2.33-2.60 (m, 6H); 2.712 (t,                       needleshaped                                                                           H, 7.99 (8.07)                                                                          1375    J = 5 Hz, 2H); 3.161 (q, J = 3 Hz, 2H);                                       6.021 (quint, J = 2 Hz,                            crystals N, 4.69 (4.87)    1H); 7.116, 7.283 (ABq, J = 9 Hz, 4H)         I a-25                                                                             (maleate)                                                                              C.sub.24 H.sub.30 N.sub.2 O.sub.2.                                                      (Nujol) (CD.sub.3 OD)                                      148.0˜150.0                                                                      C.sub.4 H.sub. 4 O.sub.4                                                                2720, 2575(sh),                                                                       1.80-2.01 (m, 4H); 2.331 (s, 3H);                                             2.48-2.63 (m, 4H); 2.712 (t,                       (iPrOH--Et.sub.2 O)                                                                    C, 72.65 (72.70)                                                                        2490(sh), 2330,                                                                       J = 7 Hz, 2H); 2.747 (t, J = 7 Hz, 2H);                                       3.162 (q, J = 3 Hz, 2H);                                    H, 7.36 (7.41)                                                                          1708, 1652, 1600                                                                      3.283 (t, J = 6 Hz, 2H); 3.329 (t, J = 7                                      Hz, 2H); 6.026 (quint,                                      N, 6.11 (6.06)                                                                          1571, 1502, 1459                                                                      J = 2 Hz, 1H); 6.50-6.64 (m, 2H);                                             6.91-7.32 (m, 6H)                             I a-26                                                                             (maleate)                                                                              C.sub.24 H.sub.30 N.sub.2 O.sub.2.                                                      (Nujol) (CDCl.sub.3)                                       191.0˜192.0                                                                      C.sub.4 H.sub.4 O.sub.4                                                                 3030, 2720, 2278                                                                      1.322 (s, 9H); 1.76-1.94 (m, 8H); 2.262                                       (t-d, J.sub.1 = 14 Hz,                             (MeOH--H.sub.2 O)                                                                      C, 66.48 (66.42)                                                                        1711, 1623, 1572                                                                      J.sub.2 = 4 Hz, 2H); 2.50-2.65 (m, 4H);                                       2.951 (d, J = 11 Hz, 2H);                          needleshaped                                                                           H, 6.61 (6.62)                                                                          1532, 1513(sh),                                                                       3.30-3.39 (m, 4H); 5.738 (brs, 1H);                                           7.378, 7.418 (ABq, J = 8 Hz,                       crystals N, 4.92 (4.84)                                                                          1485, 1463, 1435                                                                      4H)                                           I a-27                                                                             (maleate)                                                                              C.sub.23 H.sub.23 F.sub.3 N.sub.2 O.                                                    (CHCl.sub.3)                                                                          (CD.sub.3 OD)                                      152.5˜154.0                                                                      C.sub.4 H.sub.4 O.sub.4                                                                 2700-1750 (br);                                                                       2.236 (quint, J = 7 Hz, 2H); 2.934 (brs,                                      2H); 3.334 (t, J = 7 Hz,                           (MeOH--Et.sub.2 O)                                                                     H, 5.29 (5.27)                                                                          1695, 1663, 1619                                                                      2H); 2.369 (t, J = 5 Hz, 2H); 3.808 (t, J                                     = 7 Hz, 2H); 4.010 (s,                             needleshaped                                                                           N, 5.48 (5.42)                                                                          1532, 1463, 1412                                                                      2H); 4.606 (s, 2H); 6.230 (brs, 2H);                                          6.298 (brs, 1H); 7.51-7.81 (m,                     crystals F, 11.00 (11.03)                                                                        1378, 1358                                                                            9H)                                           I a-28                                                                             (maleate)                                                                              C.sub.19 H.sub.27 N.sub.2 F.sub.3.                                                      (Nujol) (CDCl.sub.3)                                       182.5˜184.0                                                                      C.sub.4 H.sub.4 O.sub.4                                                                 3483, 2723, 2679                                                                      0.952 (d, J = 7 Hz, 6H); 2.093 (quint, J                                      = 7 Hz, 3H); 2.636 (brs,                           (MeOH--Et.sub.2 O)                                                                     --        2587, 2415, 1703                                                                      2H); 2.727 (d, J = 7 Hz, 2H); 2.771 (t, J                                     = 6 Hz, 2H); 2.898 (t,                             needleshaped       1618, 1579, 1478                                                                      J = 6 Hz, 2H); 3.149 (t, J = 6 Hz, 2H);                                       3.29-3.33 (m, 2H); 6.184                           crystals           1460, 1412, 1382                                                                      (quint, J = 2 Hz, 1H); 7.474, 7.587 (ABq,                                     J = 8 Hz, 4H)                                 I a-29                                                                             (maleate)                                                                              C.sub.27 H.sub.36 N.sub.2.                                                              (Nujol) (CD.sub.3 OD)                                      183.5˜185.0                                                                      2C.sub.4 H.sub.4 O.sub.4.                                                               2340, 1708, 1619                                                                      1.330 (s, 9H); 2.424 (brs, 2H); 2.867                                         (brs, 2H); 3.204 (brs, 2H);                        (CHCl.sub.3 --MeOH)                                                                    1/10 H.sub.2 O                                                                          1568, 1528(sh),                                                                       3.370 (brs, 4H); 3.544 (brs, 4H); 3.948                                       (s, 2H); 4.403 (s, 2H);                            needleshaped                                                                           C, 67.29 (67.59)                                                                        1485, 1461                                                                            6.060 (s, 1H); 6.252 (s, 4H); 7.15-7.44                                       (m, 8H)                                            crystals H, 7.08 (7.16)                                                                N, 4.56 (4.50)                                                  __________________________________________________________________________     *.sup.1 : a solvent for recrystallization                                

EXAMPLE 30

1-[(3-methylamino)propyl]-4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridine(I a-30) ##STR32##

(1) A solution of 3.60 g of the compound (II-6) and 2.80 g of1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in thepresence of 4.26 g of K₂ CO₃ and 3.46 g of NaI at 105°-110° C. for 6hours. The reaction mixture is poured into ice water and extracted withethyl acetate. The ethyl acetate layer is washed with water, dried overMgSO₄ and evaporated under reduced pressure. The residue is subjected tocolumn chromatography with silica gel, eluting with methylenechlorde/methanol (10/1-5/1 v/v) to give 4.60 g (Yield: 82.0%) of thecompound (IV-6) as crystals. Recrystallization from methylenechloride-ether gives colorless needles. mp. 111.5°-113.0° C.

Anal Calcd. (%) for C₂₁ H₃₄ N₂ O₃.1/5H₂ O: C, 68.92; H, 9.37; N, 7.78Found: C, 68.89; H, 9.47; N, 7.65 IR(Nujol): 3320, 1715, 1700, 1535 NMR(CDCl₃) δ: 1.242 (t, J=7 Hz, 3H); 1.320 (s, 9H); 1.66-1.84 (m, 4H);2.210 (td, J₁ =13 Hz, J₂ =4 Hz, 2H) 2.45-2.60 (m, 4H); 2.877 (d, J=12Hz, 2H); 3.286 (q, J=6 Hz, 2H); 4.103 (q, J=7 Hz, 2H); 5.929 (brs, 1H);7.376,7.443 (ABq, J=8 Hz, 4H)

(2) A solution of 4.30 g of the compound (IV-6) obtained above in 35 mlof trifluoroacetic acid is refluxed for 5 hours and treated in the samemanner as Example 7(2) to prepare 4.05 g (Yield: 99%) of the compound(V-4) as an oil.

(3) To a suspension of 146 mg of lithium aluminium hydride in 15 ml ofdry ether is added dropwise a solution of 530 mg of the compound (V-4)in 15 ml of THF under stirring. After reflux for 8 hours, the excessreagents are decomposed by careful addition of aq.NaOH and filtered off.The resulting organic layer is dried and evaporated under reducedpressure to prepare 420 mg (Yield: 95.2%) of the compound (I a-30) as anoil.

IR (CHCl₃) 3290, 1602, 1510, 1470, 1445 NMR (CDCl₃): 1.321 (s, 9H);1.780 (quint, J=7 Hz, 2H); 2.444 (s, 3H); 2.48-2.62 (m, 2H); 2.532 (t,J=7 Hz, 2H); 2.672 (t, J=7 Hz, 2H); 3.152 (q, J=3 Hz, 2H); 6.0309(quint, J=2 Hz, 1H); 7.333 (s, 4H)

EXAMPLE 31

1-[N-methyl-N-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetra-hydropyridin-1-yl}propylcarbamoyl]]-2-oxopyrrolidine(I a-31) ##STR33##

A mixture of 400 mg of the compound (I a-30) obtained in Example 30 and280 mg of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 2hours. The reaction mixture is subjected to column chromatography withsilica gel, eluting with toluene/ethyl acetate (1/1)-methylenechloride/methanol (20/1) to prepare 370 mg (Yield: 68.5%) of thecompound (I a-31) as an oil. The tosylate is recrystallized from ethylacetate/methanol to prepare needles. mp. 128.0°-134.0° C.

Anal Calcd. (%) for C₂₄ H₃₅ N₃ O₂.C₇ H₈ O₃ S.H₂ O: C, 63.51; H, 7.56; N,7.16; S, 5.37 Found: C, 63.35; H, 7.72; N, 7.15; S, 5.45 IR (Nujol) cm⁻¹: 3570, 3500, 2740, 2630, 1720, 1690, 1675(sh), 1663, 1475, 1120, 1033NMR (CDCl₃) δ: 1.314 (s, 9H); 1.895 (quint, J=7 Hz, 2H); 2.071 (quint,J=7 Hz, 2H); 2.454 (t, J=8 Hz, 2H); 2.50-2.60 (m, 4H); 2.720 (t, J=5 Hz,2H); 2.995 (s, 3H); 3.174 (q, J=3 Hz, 2H); 3.461 (t, J=7 Hz, 2H) 3.735(t, J=7 Hz, 2H); 6.024 (quint, J=2 Hz, 1H); 7.244, 7.348 (ABq, J=8 Hz,4H )

EXAMPLE 32

1-[(3-methylamino)propyl]-4-(4-phenylphenyl-1,2,5,6-tetrahydropyridine(I a-32) ##STR34##

(1) A solution of 3.20 g of the compound (II-5) and 2.30 g of1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in thepresence of 3.48 g of K₂ CO₃ and 2.83 g of NaI at 105° C. for 41 hours.The reaction mixture is poured into ice water and extracted with ethylacetate. The ethyl acetate layer is washed with water, dried over MgSO₄and evaporated under reduced pressure. The residue is subjected tocolumn chromatography with silica gel, eluting with methylenechloride/methanol (10/1-5/1 v/v). The resulting purified substance isrecrystallized from methylene chloride to prepare 2.46 g (Yield: 51.0%)of the compound (IV-7). mp. 138.0°-139.0° C.

Anal Calcd. (%) for C₂₃ H₃₀ N₂ O₃ : C, 72.22; H, 7.84; N, 7.30 Found: C,72.22; H, 7.91; N, 7.32 IR (CHCl₃) cm⁻¹ : 3600, 3450, 1705, 1602, 1512,1490 NMR (CDCl₃) δ: 1.240 (t, J=7 Hz, 3H); 1.60-1.80 (m, 4H); 1.830 (s,1H); 2.195 (t-d, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.480 (d-d, J₁ 14 Hz, J₂ 2Hz, 2H); 2.524 (t, J=7 Hz, 2H); 2.850 (d, J=14 Hz, 2H); 3.280(q, J=6 Hz,2H); 4.101 (q, J=7 Hz, 2H); 6.962 (brs, 1H); 7.25-7.70 (m, 9H) 9H)

(2) A solution of 2.29 g of the compound (IV-7) in 25 ml oftrifluoroacetic acid is refluxed for 9.5 hours and treated in the samemanner as Example 7 (2) to prepare 2.08 g (Yield: 95.3%) of the compound(V-5). mp. 135.0°-138.0° C.

(3) To a solution of 1.80 g of the compound (V-5) in 26 ml of THF isadded dropwise 375 mg of lithium aluminium hydride, After reflux for 8hours, the reaction mixture is treated in the same manner as Example 29(3) to prepare (I a-32) as an oil.

EXAMPLE 33

1-[3-{4-(4-phenylphenl)-1,2,5,6-tetrahydropyridin-1-yl}propylmethylcarbamoyl]-2-oxopyrrolidine(I a-33) ##STR35##

To the compound (I a-32) obtained Example 32 is added dropwise 810 mg of1-phenoxycarbonyl-2-oxopyrrolidine, and the mixture is heated at115°-120° C. for 5 hours. The reaction mixture is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(20/1 v/v) to prepare 650 mg (Yield: 31.5%) of the compound (I a-33).The oxalate is recrystallized from i-PrOH to give needles. mp.186.0°-187.0° C. (dec.)

Anal Calcd. (%) for C₂₅ H₃₁ N₃ O₂.C₂ H₂ O₄.1/2H₂ O: C, 64.71; H, 6.52;N,7.97 Found: C, 65.10; H, 6.63; N,8.13 IR (Nujol): 3500(br), 2720,2600, 1720, 1665, 1485, 1455, 1405, 1405, 1375 NMR (CDCl₃) δ: 1.900(quint, J=7 Hz, 2H); 2.107 (quint, J=7 Hz, 2H); 2.455 (t, J=8 Hz, 2H);2.55-2.64 (m, 4H); 2.741 (t, J=5 Hz, 2H); 3.002 (s, 3H); 3.198 (q, J=3Hz, 2H); 3.469 (t, J=7 Hz, 2H); 3.737 (t, J=7 Hz, 2H); 6.124 (quint, J=2Hz, 1H) 7.3-7.6 (m, 9H)

EXAMPLE 34

1-[3-(N-methyl-N-isobutyl)aminopropyl]-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine(I a-34) ##STR36##

A mixture of 342 mg of the compound (I a-23), 1 ml of formaldehyde, and1 ml of formic acid is stirred at 70° C. for 3 hours and 40 minutes. Thereaction mixture is concentrated, and the residue is poured intoaq.NaHCO₃. The solution is extracted with methylene chloride-methanol,and the organic layer is dried over MgSO₄ and evaporated under reducedpressure. The resulting oily substance is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(19/1-5/1 v/v) to prepare 252 mg of the objective compound (I a-34). Themaleate is recrystallized from ethnol-ether to prepare 325 mg (Yield:55.2%) of colorless needles. mp. 182.0°-183.5° C.

Anal Calcd. (%) for C₂₀ H₂₉ N₂ F₃.2C₄ H₄ O₄ : C, 57.16; H, 6.32; N,4.82; F, 9.46 Found: C, 57.33; H, 6.36; N, 4.78; F, 9.72 IR (Nujol)2360, 1708, 1621, 1570, 1533, 1481, 1460, 1447(sh), 1377, 1359 NMR(CDCl₃): 0.938 (d, J=7 Hz, 6H); 1.826 (quint, J=7 Hz, 3H); 2.212 (d, J=7Hz, 2H); 2.309 (s, 3H); 2.513 (t, J=7 Hz, 2H); 2.548 (t, J=7 Hz, 2H);2.58, 2.63 (m, 2H); 2.747 (t, J=5 Hz, 2H); 3.208 (q, J=3 Hz, 2H); 6.161(quint, J=2 Hz, 1H); 7.474, 7.567 (ABq, J=8 Hz, 4H)

EXAMPLE 35

4-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]morpholine(I a-35) ##STR37##

(1) A mixture of 1.09 g of the compound (IV-2) obtained in Example 18and 1.4 g of morpholine is refluxed for 4 hours. After removal of theexcess reagent under reduced pressure, the residue is poured into aq.Na₂SO₄ and evaporated. The residue is purified by column chromatographywith silica gel, eluting with mthylene chloride/methanol (20/1 v/v). Thehydrochloride of the compound (III-19) is crystallized from methylenechloride-ether to prepare 850 mg (Yield: 66.3%) of needles. mp. 242° C.(dec.)

NMR (CDCl₃.CD₃ OD=10/1): 1.307 (s, 9H); 2.10-2.22 (m, 2H); 2.48-2.55 (m,4H); 2.760 (td, J₁ =15 Hz, J₂ =4 Hz, 2H); 3.06-3.15 (m, 4H); 3.25-3.50(m, 4H); 3.731 (t, J=5 Hz, 4H); 7.387, 7.454 (ABq, J=9 Hz, 4H)

(2) A solution of 880 mg of the compound (III-19) in 10 ml oftrifluoroacetic acid is refluxed for 8 hours and evaporated underreduced pressure. The residue is poured into aq. sodiumhydrogencarbonate, and extracted with methylene chloride. The organiclayer is washed with saline, dried over Na₂ SO₄ and evaporated. Theresidue is purified by column chromatography followed by crystallizationas the maleate. Recrystallization from methanol gives 760 mg (Yield:97.5%) of redish needles. mp. 213.0°-214.5° C. (dec.)

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O.2C₄ H₄ O₄ : C, 62.63; H, 7.35; N, 4.93Found: C, 62.70; H, 7.37; N, 4.87 IR (Nujol): 2300 (br); 1717, 1622,1675, 1535, 1500, 1455, 1458, 1450(sh) NMR (CDCl₃): 1.314 (s, 9H); 1.783(quint, J=7 Hz, 2H); 2.36, 2.63 (m, 8H); 2.709 (t, J=5 Hz, 2H); 3.164(q, J=3 Hz, 2H); 3.725 (t, J=5 Hz, 2H); 6.031 (quint, J=1 Hz, 1H); 7.330(s, 4H)

EXAMPLE 36-71

The reaction is performed in the same manner as Example 1 to prepare thecompound (I a). The reaction conditions are shown in Table 7 and 8.Further the physical constants of the compound (I a) obtained in Example36-71 are shown in Table 9.

                                      TABLE 7                                     __________________________________________________________________________    (Step 1)                                                                         start-                            reac-                                       ing                               tion                                     Ex-                                                                              mate-                             condi-                                                                             purifi-                                                                             g (%)                         am.                                                                              rial                  DMF  K.sub.2 CO.sub.3                                                                  NaI                                                                              tion(1)                                                                            cation                                                                              Compd.                                                                             m.p.                     No.                                                                              X=  R(CH.sub.2).sub.n Y (VI)                                                                        (ml) (g) (g)                                                                              (°C. hr.)                                                                   condition                                                                           No.  (°C.)                                                                      IR                   __________________________________________________________________________                                                             (cm.sup.-1)           ##STR38##                                                                    36 Me(p) 2.50 g (II-8)                                                                ##STR39##        35   4.53                                                                               2.95                                                                            105-110 7 hr.                                                                      CH.sub.2 Cl.sub.2 / MeOH =                                                          3.46 (76.4) (III-20)                                                               116.0˜                                                                      (CHCl.sub.3)                                                                  3600, 3320,                                                                   1713, 1688 (sh),                                                              1680, 1545,                                                                   1490                 37 Me(p) 2.34 g (II-8)                                                                ##STR40##        25   4.21                                                                              2.74                                                                             105 6 hr.                                                                          toluene/ ethyl ac- etate =                                                    20/1-10/1                                                                           3.07 (70.0) (III-21)                                                               143.5˜                                                                      (CHCl.sub.3)                                                                  3600, 3320,                                                                   1715, 1618,                                                                   1550-1520            38 Me(m)                                                                             (VI-1) 2.35 g     30   3.18                                                                              2.59                                                                             105-110                                                                            CH.sub.2 Cl.sub.2/                                                                  1.70 --  (CHCl.sub.3)            1.85 g                            8 hr.                                                                              MeOH =                                                                              (49.0)   3600, 3320,             (II-9)                                 10/1  (III-22) 1715, 1680,                                                                   1608, 1545,                                                                   1490, 1470           39 Me(o)                                                                             (VI-1) 2.68 g     35   4.53                                                                              2.95                                                                             105-110                                                                            CH.sub.2 Cl.sub.2 /                                                                 3.18 --  (CHCl.sub.3)            2.50 g                            7 hr.                                                                              MeOH =                                                                              (67.5)   3600, 3320,             (II-10)                                10/1  (III-23) 1712, 1680,                                                                   1600, 1545,                                                                   1489, 1470                                                                    1460                 40 3,4-                                                                              (VI-1) 2.09 g     35   2.82                                                                              2.29                                                                             105  CH.sub.2 Cl.sub.2 /                                                                 2.56 --  --                      di-Me                             7 hr.                                                                              MeOH =                                                                              (67.2)                           2.10 g                                 10/1  (III-24)                         (II-11)                                                                    41 3.5-                                                                              (VI-1) 2.81 g     35   3.79                                                                              3.08                                                                             105° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 3.81 --  (CHCl.sub.3)            di-Me                             6 hr.                                                                              MeOH =                                                                              (74.4)   3595, 3310,             2.82 g                                 10/1  (III-25) 1715, 1680,             (II-12)                                               1590, 1565,                                                                   1545, 1489,                                                                   1470, 1460.          42 Cl(m)                                                                             (VI-1) 2.49 g     30   4.18                                                                              2.72                                                                             105- CH.sub.2 Cl.sub.2 /                                                                 3.78 90.5˜                                                                       (CHCl.sub.3)            2.70 g                            110° C.                                                                     MeOH =                                                                              (81.8)                                                                             91.5                                                                              3600, 3220,             (II-13)                           7 hr.                                                                              20/1-10/1                                                                           (III-26) 1713, 1658,                                                                   1595, 1545,                                                                   1490, 1470,                                                                   1460                 43 Cl(m)                                                                             (VI-7) 2.31 g     30   4.18                                                                              2.72                                                                             105- CH.sub.2 Cl.sub.2 /                                                                 3.30 94.0-                                                                             (Nujol)                 2.70 g                            110° C.                                                                     MeOH =                                                                              (74.3)                                                                             98.0                                                                              3280, 2720-             (II-13)                           7 hr.                                                                              10/1  (III-27) 2520, 1713,                                                                   1685, 1600,                                                                   (sh), 1588,                                                                   1560                 44 Cl(o)                                                                             (VI-1) 2.42 g     30   4.08                                                                              2.65                                                                             105-110                                                                            ethyl ac-                                                                           2.10 --  (CHCl.sub.3)            2.50 g                            6 hr.                                                                              etate/tol-                                                                          (46.7)   3580, 3320,             (II-14)                                uene =                                                                              (III-28) 1715, 1680,                                                    1/1            1547                                                           CH.sub.2 Cl.sub.2 /                                                           MeOH =                                                                        15/1                                45 Cl(o)                                                                             (VI-7) 1.28 g     20   2.32                                                                              1.51                                                                             105-110                                                                            CH.sub.2 Cl.sub.2 /                                                                 0.840                                                                              --  (CHCl.sub.3)            1.45 g                            6 hr.                                                                              MeOH =                                                                              (34.1)   3580, 3220,             (II-14)                                15/1  (III-29) 1715, 1680,                                                                   1545(sh),                                                                     1540(sh),                                                                     1525                 46 3.5-                                                                              (VI-1) 3.0 g      35   4.04                                                                              3.28                                                                             105°C.                                                                      CH.sub.2 Cl.sub.2 /                                                                 5.25 138.0-                                                                            (CHCl.sub.3)            diCl                              7.0 hr.                                                                            MeOH =                                                                              (86.8)                                                                             140.0                                                                             3595, 3310,             3.86 g                                 10/1  (III-30) 1715, 1680,             (II-15)                                               1590, 1565,                                                                   1545                 47 Br(p)                                                                             (VI-1) 1.96 g     25   2.64                                                                              2.15                                                                             105° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 3.16 --  (CHCl.sub.3)            2.57 g                            8 hr.                                                                              MeOH =                                                                              (77.9)   3590, 3310,             (II-16)                                10/1  (III-31) 1713, 1680,                                                                   1545, 1489,                                                                   1460                 48 F(p)                                                                              (VI-1) 4.20 g     50   7.08                                                                              4.61                                                                             105- CH.sub.2 Cl.sub.2 /                                                                 4.96 102.5-                                                                            (CHCl.sub.3)            4.00 g                            110° C.                                                                     MeOH =                                                                              (66.5)                                                                             104.0                                                                             3600, 3320,             (II-17)                           6.0 hr.                                                                            15/1-8/1                                                                            (III-32) 1713, 1680,                                                                   1545, 1510,                                                                   1489                 49 F(p)                                                                              (VI-7) 2.25 g     25   4.08                                                                              2.65                                                                             105° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 2.78 118.0-                                                                            (CHCl.sub.3)            2.30 g                            6 hr.                                                                              MeOH =                                                                              (67.4)                                                                             119.0                                                                             3600, 3320,             (II-17)                                10/1  (III-33) 1713, 1680,                                                                   1605, 1545,                                                                   1510, 1489           50 CF.sub.3                                                                          (VI-1) 2.56 g     50   3.46                                                                              2.81                                                                             105- CH.sub.2 Cl.sub.2 /                                                                 5.20 238.5-                                                                            (Nujol)                 (m)                               110°  C.                                                                    MeOH =                                                                              (92.9)                                                                             240.5                                                                             3350, 2650,             Cl(p)                             9 hr.                                                                              20/1-10/1                                                                           (III-34) 2525, 2450,             3.50 g                                                1720, 1677,             (II-18)                                               1557                 51 CF.sub.3                                                                          (VI-7) 2.38 g     50   3.46                                                                              2.81                                                                             105-110                                                                            CH.sub.2 Cl.sub.2 /                                                                 4.75 255.0-                                                                            (Nujol)                 (m)                               15 hr.                                                                             MeOH =                                                                              (87.6)                                                                             257.0                                                                             3400, 3260,             Cl(p)                                  20/1-10/1                                                                           (III-35) 2640, 2500,             3.50 g                                                2430, 1713,             (II-18)                                               1672, 1547            ##STR41##                                                                    52 2.80 g                                                                            (VI-1) 2.64 g     36   4.46                                                                              2.90                                                                             105-110                                                                            CH.sub.2 Cl.sub.                                                                    3.55 122.0˜                                                                      (CHCl.sub.3)            (II-                              8 days                                                                             MeOH =                                                                              (71.3)                                                                             123.0                                                                             3590, 3320,             19)*.sup.1                             10/1  (III-36) 1713, 1680,                                                                   1544, 1490,                                                                   1470,                                                                         1460(sh),                                                                     1450                 53 2.10 g                                                                            (VI-1) 1.70 g     30   1.73                                                                              2.50                                                                             105  CH.sub.2 Cl.sub.2 /                                                                 3.00 --  (CHCl.sub.3)            (II-                              7 days                                                                             MeOH =                                                                              (85.7)   3600, 3320,             20)*.sup.2                             10/1  (III-37) 1712, 1680,                                                                   1543                 __________________________________________________________________________     ##STR42##                                                                     ##STR43##                                                                

    54 Cl(p)                                                                             (VI-5) 1.03 g     10   1.63                                                                              1.06                                                                             90   CH.sub.2 Cl.sub.2 /                                                                 1.37 111.5-                                                                            (CDCl.sub.3)            1.00 g                            12 hr.                                                                             MeOH =                                                                              (74.0)                                                                             112.0                                                                             3600, 3280,             (II-21)                                20/1-10/1                                                                           (III-38) 1702, 1698,                                                                   1530, 1645,                                                                   1495, 1480,                                                                   1463                 55 Cl(p) 2.0 g (II-21)                                                                                 25   3.26                                                                              2.12                                                                             90-95 10 hr.                                                                       CH.sub.2 Cl.sub.2 / MeOH =                                                          1.75 (48.7) (III-39)                                                               128.0- 129.0                                                                      (CDCl.sub.3)                                                                  3600, 3280,                                                                   1525, 1492,                                                                   1480, 1460           56 t-Bu(p) 1.00 g (II-6)                                                              ##STR44##        10   K.sub.2 CO.sub.3  1.184                                                           NaI 0.96                                                                         100° C. 3 hr.                                                               CH.sub.2 Cl.sub.2 / MeOH/                                                     NH.sub.4 OH = 64/8/1                                                                1.13 (71.0) (III-40)                                                               --  (CHCl.sub.3)                                                                  3590, 2498,                                                                   1510, 1470,                                                                   1455, 1399           57 Me(p)                                                                             (VI-9) 1.10 g     10   K.sub.2 CO.sub.3                                                                  NaI                                                                              100° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 1.445                                                                              --  (CHCl.sub.3)            1.00 g                     1.45                                                                              1.18                                                                             2.5 hr.                                                                            MeOH/ (83.6)   3580, 2498,             (II-8)                                 NH.sub.4 OH =                                                                       (III-41) 1510, 1463,                                                    64/8/1         1450, 1375           58 tBu(p) 0.81 g (II-6)                                                               ##STR45##        12   K.sub.2 CO.sub.3  0.96                                                            NaI  0.78                                                                        100° C. 2.7                                                                 CH.sub.2 Cl.sub.2 / MeOH/                                                     NH.sub.4 OH = 64/8/1                                                                1.053 (84.6) (III-42)                                                              --  (CHCl.sub.3)                                                                  3580, 2498,                                                                   1510, 1463,                                                                   1450, 1375           59 tBu(p) 0.727 g (II-6)                                                              ##STR46##        11   K.sub.2 CO.sub.3  0.86                                                            NaI 0.70                                                                         100° C. 2.5                                                                 --.   0.736 (62.4) (III-43)                                                              --  (CHCl.sub.3)                                                                  3630, 3590,                                                                   3390, 2499,                                                                   1506, 1467,                                                                   1440, 1421,                                                                   1399                 60 Me(p)                                                                             HO(CH.sub.2).sub.3 Cl (VI-12)                                                                   --     Et.sub.3 N                                                                         140° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 8.51 g                                                                             183.0-                                                                            (CHCl.sub.3)            10.2 g                                                                            5.81 ml                  11.16 ml                                                                           4.0 hr.                                                                            MeOH =                                                                              (64.0)                                                                             185.0                                                                             3597, 3220,             (II-8)                                 9/1   (III-44) 1513, 1470,                                                                   1452, 1437,                                                                   1423, 1397           61 Me(p)                                                                             (VI-3) 964 mg      15  K.sub.2 CO.sub.3                                                                  NaI                                                                              105° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 0.74 g                                                                             170.0˜                                                                      (CHCl.sub.3)            0.964 g                    1.40 g                                                                            1.14                                                                             5.75 hr.                                                                           MeOH =                                                                              (41.7)                                                                             172.5                                                                             3675, 3599,             (II-8)                         g       9/1   (III-45) 3465, 3285,                                                    CH.sub.2 Cl.sub.2 /                                                                          2465, 1631,                                                    MeOH/          1521, 1488,                                                    NH.sub.4 OH =  1478, 1462,                                                    64/8/1         1457(sh),                                                                     1439(sh),                                                                     1402                 62 Ph(p)                                                                             (VI-3) 0.70 g     11   K.sub.2 CO.sub.3                                                                  NaI                                                                              105° C.                                                                     CH.sub.2 Cl.sub.2 /                                                                 616 mg                                                                             225.0˜                                                                      (Nujol)                 0.93 g                     1.02 g                                                                            0.83                                                                             5.75 hr.                                                                           MeOH =                                                                              (41.0)                                                                             228.0                                                                             3300, 3055,             (II-5)                         g       10/1  (III-46)                                                                           (dec.)                                                                            3030, 2810,                                                    CH.sub.2 Cl.sub.2 /                                                                          2770, 2670,                                                    MeOH/          1606, 1528,                                                    NH.sub.4 OH =  1487, 1471,                                                    128/16/        1456, 1448                                                     1 = 32/6/1                          63 CF.sub.3 (p) 1.50 g (II-2)                                                         ##STR47##        20   K.sub.2 CO.sub.3  1.69 g                                                          NaI 1.38 mg                                                                      105° C. 8.0                                                                 CH.sub.2 Cl.sub.2 / MeOH =                                                    20/1-10/1                                                                           0.56 g (19.1) (III-47)                                                             142.5- 144.0                                                                      (CHCl.sub.3)                                                                  3690, 3600,                                                                   1637(sh) 1632,                                                                1587, 1552,                                                                   1510(sh),                                                                     1495,1440            64 Me(p) 1.44 g (II-8)                                                                ##STR48##        CH.sub.2 Cl.sub.2  20                                                                Et.sub.3 N 1.16 ml                                                                 room tempera- ture 92                                                              CH.sub.2 Cl.sub. 2 / MeOH/                                                    NH.sub.4 OH = 128/10/1˜                                                 64/8/1                                                                              2.11 g (88.4) (III-48)                                                             --  --                   __________________________________________________________________________    Exam.            DMF  K.sub.2 CO.sub.3                                                                  NaI reaction                                                                              purification                                                                             g (%)                        No. (II) R(CH.sub.2).sub.n Y (VI)                                                              ml   g   g   condition                                                                             condition (1)                                                                            (III)  m.p.                  __________________________________________________________________________                                                            (°C.)          65  (II-6)                                                                             (VI-7) 3.00 g                                                                         45   4.35                                                                              3.54                                                                              105° C. 8 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH                                                                  4.90 (73.5)                                                                          219.0˜222.0         3.67 g                            29/1˜9/1                                                                           (III-49)                     66  (II-1)                                                                             (VI-7) 3.07 g                                                                         45   4.04                                                                              3.28                                                                              105° C. 9 hr                                                                   CH.sub.2 Cl.sub.2 /MeOH                                                                  5.57 (95.0)                                                                          232.0˜239.0         3.60 g                            10/1       (III-50)                     67  (II-2)                                                                             (VI-7) 3.34 g                                                                         45   4.83                                                                              3.93                                                                              105° C. 9 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH                                                                  6.11 (87.4)                                                                          266.0˜268.0         4.70 g                            15/1˜10/1                                                                          (III-51)                     68  (II-16)                                                                            (VI-7) 2.50 g                                                                         35   3.62                                                                              2.95                                                                              105° C. 12 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH                                                                  4.50 (83.7)                                                                          230.0˜232.0         3.36 g                            10/1       (III-52)                     69  (II-5)                                                                             (VI-7) 3.00 g                                                                         45   4.35                                                                              3.54                                                                              105° C. 8 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH                                                                  5.61 (80.3)                                                                          233.0˜238.0         3.99 g                            39/1˜19/1                                                                          (III-53)                     70  (II-3)                                                                             (VI-1) 3.00 g                                                                         45   4.35                                                                              3.54                                                                              105° C. 6.5 hr                                                                 CH.sub.2 Cl.sub.2 /MeOH                                                                  5.34 (82.7)                                                                          203.0˜207.5         3.45 g                            39/1˜9/1                                                                           (III-54)                     71  (II-22)*                                                                           (VI-1) 2.23 g                                                                         30   3.01                                                                              2.44                                                                              105° C. 8.5 hr                                                                 CH.sub.2 Cl.sub.2 /MeOH                                                                  1.35 (30.5)                                                                          95.0˜96.5           2.60 g                            10/1˜5/1                                                                           (III-55)                     __________________________________________________________________________     ##STR49##                                                                

                                      TABLE 8                                     __________________________________________________________________________    (Step 2)                                                                      (III)                    purification  Product                                (g)  acid   solvent (ml)                                                                         reflux time                                                                         condition (2) g (%)                                  __________________________________________________________________________    (III -20)                                                                          TsOH.H.sub.2 O                                                                       toluene (60)                                                                         13 hr.                                                                              ethyl acetate I a-36                                 2.53 g                                                                             (2.68 g)                                                                             CH.sub.2 Cl.sub.2 (20)                                                                     CH.sub.2 Cl.sub.2 /MeOH = 10/1                                                              2.17 g                                                                        (90.3)                                 (III -21)                                                                          TsOH.H.sub.2 O                                                                       toluene (300)                                                                        30 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              I a-37                                 2.66 g                                                                             (2.93 g)                                                                             CH.sub.2 Cl.sub.2 (50)     2.27 g                                                                        (90.0)                                 (III -22)                                                                          TsOH.H.sub.2 O                                                                       toluene (300)                                                                        48 hr.                                                                              ethyl acetate I a-38                                 3.30 g                                                                             (3.49 g)            CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              2.50 g                                                                        (80.0)                                 (III -23)                                                                          TsOH.H.sub.2 O                                                                       toluene (250)                                                                        69 hr.                                                                              toluene/      I a-39                                 3.18 g                                                                             (4.21 g)                                                                             CH.sub.2 Cl.sub.2 (60)                                                                     ethyl acetate = 1/1                                                                         2.96 g                                                          CH.sub.2 Cl.sub.2 /MeOH =  20/1                                                             (quantitative)                         (III -24)                                                                          CF.sub.3 COOH                                                                        --     8  hr.                                                                              toluene/      I a-40                                 2.56 g                                                                             (27 ml)             ethyl acetate = 30/1                                                                        2.40 g                                                                        (98.0)                                 (III -25)                                                                          CF.sub.3 COOH                                                                        --     8.5                                                                              hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                              I a-41                                 3.80 g                                                                             (26 ml)                           3.50 g                                                                        (96.8)                                 (III -26)                                                                          TsOH.H.sub.2 O                                                                       toluene (250)                                                                        27 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              I a-42                                 3.16 g                                                                             (3.16 g)                                                                             CH.sub.2 Cl.sub.2 (70)     2.20 g                                                                        (73.1)                                 (III -27)                                                                          TsOH.H.sub.2 O                                                                       toluene (200)                                                                        48 hr.                                                                              toluene/      I a-43                                 2.45 g                                                                             (2.55 g)                                                                             CH.sub.2 Cl.sub.2 (50)                                                                     ethyl acetate = 1/1                                                                         1.87 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (80.2)                                 (III -28)                                                                          TsOH.H.sub.2 O                                                                       toluene (100)                                                                        29 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              I a-44                                 2.10 g                                                                             (1.60 g)            ethyl acetate 1.480 g                                                                       (73.8)                                 (III -29)                                                                          TsOH.H.sub.2 O                                                                       toluene (60)                                                                         31 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                              I a-45                                 0.84 g                                                                             (0.52 g)                          0.80 g                                                                        (quantitative)                         (III -30)                                                                          CF.sub.3 COOH                                                                        --     39 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                              I a-46                                 2.10 g                                                                             (10 ml)                           1.34 g                                                                        (70.2)                                 (III -31)                                                                          CF.sub.3 COOH                                                                        --     8  hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              I a-47                                 3.51 g                                                                             (36 ml)                           2.80 g                                                                        (92.9)                                 (III -32)                                                                          TsOH.H.sub.2 O                                                                       toluene (250)                                                                        26.5                                                                             hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              I a-48                                 4.14 g                                                                             (3.25 g)                          3.16 g                                                                        (80.3)                                 (III -33)                                                                          TsOH.H.sub.2 O                                                                       toluene (160)                                                                        16 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                              I a-49                                 1.93 g                                                                             (2.10 g)                                                                             CH.sub.2 Cl.sub.2 (60)     1.50 g                                                                        (81.9)                                 (III -34)                                                                          CF.sub.3 COOH                                                                        --     25 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH =                                                                   I a-50                                 3.10 g                                                                             (35 ml)             30/1-20/1     2.80 g                                                                        (94.1)                                 (III -35)                                                                          CF.sub.3 COOH                                                                        --     19.5                                                                             hr.                                                                              CH.sub.2 Cl.sub.2 MeOH =                                                                    I a-51                                 2.70 g                                                                             (35 ml)             50/1-20/1     2.40 g                                                                        (92.7)                                 (III -36)                                                                          TsOH.H.sub.2 O                                                                       toluene (280)                                                                        26 hr.                                                                              toluene =     I a-52                                 4.09 g                                                                             (4.03 g)                                                                             CH.sub.2 Cl.sub.2 (70)                                                                     ethyl acetate = 3/1                                                                         3.76 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (96.4)                                 (III -37)                                                                          CF.sub.3 COOH                                                                        --     8  hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 25/1                                                              I a-53                                 3.00 g                                                                             (30 ml)                           2.57 g                                                                        (89.5)                                 (III -38)                                                                          TsOH.H.sub.2 O                                                                       benzene (150)                                                                        23 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH =                                                                   I a-54                                 2.86 g                                                                             (2.76 g)                                                                             CH.sub.2 Cl.sub.2 (50)                                                                     10/1-20/1     1.48 g                                                                        (48.7)                                 (III -39)                                                                          TsOH.H.sub.2 O                                                                       benzene (150)                                                                        25 hr.                                                                              toluene/      I a-55                                 1.00 g                                                                             (1.00 g)                                                                             toluene (100)                                                                              ethyl acetate =  1/1                                                                        0.93 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (97.7)                                 (III -40)                                                                            CF.sub.3 COOH                                                                        1.0  hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                           I a-56                                1.134 g                                                                              (10 ml)          64/8/1          1.416 g                                                                       (79.3)                                (III -41)                                                                            CF.sub.3 COOH                                                                        1.5  hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                           I a-57*                               1.445 g                                                                              (10 ml)          64/8/1          1.787 g                                                                       (75.1)                                (III -42)                                                                            CF.sub.3 COOH                                                                        50   min. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                           I a-58*                               1.002 g                                                                              (10 ml)          64/8/1          1.17 g                                                                        (69.8)                                (III -43)                                                                            CF.sub.3 COOH                                                                        1    hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                           I a-59*                               0.722 g                                                                              (6 ml)           128/12/1-64/8/1 0.881 g                                                                       (64.6)                                (III -44)                                                                            CF.sub.3 COOH                                                                        3.17 hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                           I a-60                                12.82 g                                                                              (38.3 ml)        128/16/1-32/6/1 7.719 g                                                                       (64.9)                                (III -45)                                                                            CF.sub.3 COOH                                                                        1.5  hr.  CH.sub.2 Cl.sub. 2 /MeOH/NH.sub.4 OH                                                          I a-61*                               721 mg (10 ml)          128/16/1        664 mg                                                                        (73.1)                                (III -46)                                                                            CF.sub.3 COOH                                                                        1    hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                     I a-62*                               766 mg (10 ml)          19/1˜9/1  572 mg                                                                        (60.5)                                (III -47)                                                                            CF.sub.3 COOH                                                                        48   hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                     I a-63                                540 mg (8 ml)           30/1˜10/1 529 mg                                                                        (69.2)                                (III -48)                                                                            CF.sub.3 COOH                                                                        1.25 hr.  CH.sub.2 Cl.sub.2 /MeOH = 19/1                                                                I a-64                                2.105 g                                                                              (5 ml) room                      1.693 g                                             temperature               (85.3)                                (III -49)                                                                            CF.sub.3 COOH                                                                        50   min. CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                                I a-65                                2.87 g (35 ml)                          2.61 g                                                                        (86.7)                                (III -50)                                                                            CF.sub.3 COOH                                                                        8    hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                     I a-66                                2.85 g (30 ml)          20/1-10/1       2.70 g                                                                        (98.6)                                (III -51)                                                                            CF.sub.3 COOH                                                                        3    days.                                                                              CH.sub. 2 Cl.sub.2 /MeOH =                                                                    I a-67                                3.85 g (50 ml)          15/1-10/1       3.53 g                                                                        (96.0)                                (III -52)                                                                            CF.sub.3 COOH                                                                        7    hr.  CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                                I a-68                                1.75 g (25 ml)                          1.54 g                                                                        (92.0)                                (III -53)                                                                            CF.sub.3 COOH                                                                        50   min. CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                                I a-69                                2.98 g (34 ml)                          2.71 g                                                                        (87.1)                                (III -54)                                                                            CF.sub.3 COOH                                                                        50   min. toluene/acetone =                                                                             I a-70                                2.62 g (33 ml)          9/1-3/1         2.41 g                                                                        (87.5)                                (III -55)                                                                            CF.sub.3 COOH                                                                        2.5  hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                     I a-71                                1.58 g (20 ml)          15/1-7/1        1.28 g                                                                        (49.5)                                __________________________________________________________________________     *: maleate                                                               

                                      TABLE 9                                     __________________________________________________________________________    Compd.                                                                             m.p. (°C.)                                                                      Anal. Calcd. (%)                                                No.  (solvent*)                                                                             Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                 __________________________________________________________________________    I a-36                                                                             130.5-132.0                                                                            C.sub.19 H.sub.25 N.sub.3 O.sub.2 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 69.42 (69.70)                                                                        3310, 1713, 1680                                                                      2.020 (quint, J = 8 Hz, 2H); 2.329 (s,                                        3H, J = 7 Hz, 2H);                                          H, 7.65 (7.70)                                                                          1545, 1489, 1460                                                                      2.56-2.59 (m, 4H); 2.671 (t, J = 7 Hz,                                        2H); 2.766 (t, J = 6 Hz, 2H);                               N, 12.76 (12.83)  3.217 (q, J = 3 Hz, 2H); 3.510 (q, J = 7                                      Hz, 2H); 3.859 (t,                                                            J = 7 Hz, 2H); 6.016 (quint, J = 3 Hz,                                        1H); 7.116 (d, J = 8                                                          Hz, 2H); 7.284 (d, J = 8 Hz, 2 H); 8.596                                      (br, 1H)                                      I a-38                                                                             1.61.5-163.0                                                                           C.sub.22 H.sub.29 N.sub.3 O.sub.6 :                                                     (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 60.86 (61.24)                                                                        3330, 2600, 2500                                                                      1.782 (quint, J - 7 Hz, 2H); 1.969                                            (quint, J = 8 Hz, 2H); 2.302                       (oxalate)                                                                              H, 6.79 (6.77)                                                                          1717, 1645, 1605                                                                      (s, 3H); 2.44-2.59 (m, 6H); 2.658 (t, J =                                     6 Hz, 2H); 3.111                                            N, 9.51 (9.74)                                                                          1533, 1485, 1460                                                                      (q, J = 3 Hz, 2H); 3.347 (q, J = 7 Hz,                                        2H); 3.813 (t, J = 7 Hz,                                                      2H); 5.999 (quint, J = 3 Hz, 1H);                                             6.00-7.02 (m, 1H); 7.14-7.16 (m,                                              3H); 8.456 (brs, 1H)                          I a-39                                                                             146.0-147.0                                                                            C.sub.22 H.sub.29 N.sub.3 O.sub.6 :                                                     (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 61.08 (61.24)                                                                        3300, 2600(br),                                                                       1.873 (quint, J = 7 Hz, 2H); 2.030                                            (quint, J = 8 Hz, 2H); 2.297                       (oxalate)                                                                              H, 6.70 (6.77)                                                                          1708, 1683, 1548                                                                      (s, 3H); 2.38-2.48 (m, 2H); 2.593 (t, J =                                     7 Hz, 2H); 2.606 (t,                                        N, 9.71 (9.74)                                                                          1490(sh), 1460                                                                        J = 8 Hz, 2H); 2.746 (t, J = 6 Hz, 2H);                                       3.184 (q, J = 3 Hz, 2H);                                                      3.402 (quint, J = 7 Hz, 2H); 5.531                                            (quint, J = 2 Hz, 1H);                                                        7.11-7.17 (m, 4H); 8.519 (brs, 1H)            I a-40                                                                             146.5-147.5                                                                            C.sub.25 H.sub.33 N.sub.3 O.sub.6                                                       (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 63.40 (63.68)                                                                        3330, 2420-2300,                                                                      1.825 (quint, J = 8 Hz, 2H); 2.020                                            (quint, J = 7 Hz, 2H); 2.240                       (maleate)                                                                              H, 6.99 (7.05)                                                                          1700, 1620, 1575                                                                      (s, 3H); 2.254 (s, 3H); 2.48-2.56 (m,                                         4H); 2.594                                                  N, 3.87 (8.91)                                                                          1530, 1460, 1450                                                                      (t, J = 8 Hz, 2H); 2.697 (t, J = 5 Hz,                                        2H); 3.147 (q, J = 3 Hz, 2H);                                         (sh)    3.390 (q, J = 7 Hz, 2H); 3.859 (t, J = 7                                      Hz, 2H); 6.002 (quint,                                                        J = 2 Hz, 1H); 7.04-7.16 (m, 3H); 8.489                                       (brs, 1H)                                     I a-41                                                                             159.0-160.0                                                                            C.sub.25 H.sub.33 N.sub.3 O.sub.6                                                       (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 63.71 (63.38)                                                                        3290, 2500-2300,                                                                      1.821 (quint, J = 7 Hz, 2H); 2.013                                            (quint, J = 8 Hz, 2H); 2.300                       (maleate)                                                                              H, 7.05 (7.05)                                                                          1720(sh), 1710,                                                                       (s, 6H); 2.48-2.55 (m, 4H); 2.592 (t, J =                                     7 Hz, 2H); 2.690                                            N, 8.86 (8.91)                                                                          1685, 1620, 1600                                                                      (t, J = 6 Hz, 2H); 3.142 (q, J = 3 Hz,                                        2H); 3.385 (q, J = 7 Hz,                                              (sh), 1577, 1550                                                                      2H); 3.855 (d-d, J.sub.1 = 8 Hz, J.sub.2                                      =                                                                     1513    7 Hz, 2H); 6.014 (quint, J = 2 Hz, 1H);                                       6.878 (s, 1H); 6.998 (s, 2H)                  I a-42                                                                             155.5-157.0                                                                            C.sub.23 H.sub.28 N.sub.3 O.sub.6 Cl                                                    (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 57.74 (57.80)                                                                        3310, 2350, 2260                                                                      1.825 (quint, J = 7 Hz, 2H); 2.022                                            (quint, J = 8 Hz, 2H); 2.49-2.56                   (maleate)                                                                              H, 5.84 (5.90)                                                                          1715, 1682, 1585                                                                      (m, 4H); 2.538 (t, J = 7 Hz, 2H); 2.709                                       (t, J = 6 Hz); 3.159                                        N, 8.78 (8.79)                                                                          1520, 1485(sh),                                                                       (q, J = 3 Hz, 2H); 3.389 (q, J = 7 Hz,                                        2H); 3.861 (t, J = 7 Hz, 2H);                               Cl, 7.14 (7.42)                                                                         1455    6.084 (quint, J = 2 Hz, 1H); 7.18-7.30                                        (m, 3H); 7.346 (s, 1H);                                                       8.499 (brs, 1H)                               I a-43                                                                             102.0-103.5                                                                            C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (ethyl acetate/                                                                        C, 61.99 (62.15)                                                                        3310, 1715, 1680                                                                      2.024 (quint, J = 7 Hz, 2H); 2.55-2.64                                        (m, 4H); 2.673                                     Et.sub.2 O)                                                                            H, 6.31 (6.37)                                                                          1595, 1545, 1489                                                                      (t, J = 7 Hz, 2H); 2.766 (t, J = 6 Hz,                                        2H); 3.218 (q, J = 3 Hz,                                    N, 12.07 (12.08)                                                                        1460    2H); 3.504 (q, J = 6 Hz, 2H); 2.766 (t, J                                     = 6 Hz, 2H); 3.218 (q,                                      Cl, 9.96 (10.19)  3.860 (t, J = 7 Hz, 2H); 6.082 (quint, J                                      = 2 Hz, 1H); 7.19-7.27                                                        (m, 3H); 7.361 (s, 1H); 8.615 (brs, 1H)       I a-44                                                                             140.5-142.0                                                                            C.sub.23 H.sub.28 N.sub.3 O.sub.5 Cl.                                                   (Nujol) (CDCl.sub.3)                                       (iPrOH)  1/5 H.sub.2 O                                                                           3280, 2580, 2360                                                                      1.846 (quint, J = 7 Hz, 2H); 2.048                                            (quint, J = 8 Hz, 2H); 2.47-2.51                   (maleate)                                                                              C, 57.35 (57.37)                                                                        1715, 1690, 1620                                                                      (m, 2H); 2.566 (t, J = 8 Hz, 2H); 2.606                                       (t, J = 8 Hz, 2H); 2.728 (t,                                H, 5.87 (5.94)                                                                          1580, 1545, 1490                                                                      J = 6 Hz, 2H); 3.172 (q, J = 3 Hz, 2H);                                       3.397 (q, J = 7 Hz,                                         N, 8.67 (8.37)                                                                          (sh), 1460                                                                            2H); 3.865 (t, J = 7 Hz, 2H); 5.656                                           (quint, J = 2 Hz);                                          Cl, 7.72 (7.36)   7.15-7.37 (m, 4H); 8.510 (brs, 1H)            I a-45                                                                             142.0-143.5                                                                            C.sub.22 H.sub.26 N.sub.3 O.sub.6 Cl                                                    (Nujol) (CDCl.sub.3)                                       (maleate)                                                                              C, 56.54 (56.96)                                                                        3300, 2580-2400,                                                                      2.007 (t, quint, J = 7 Hz, 2H); 2.35-2.57                                     (m, 2H); 2.610 (t, J = 8                                    H, 5.89 (5.65)                                                                          1710, 1682, 1617                                                                      Hz); 2.746 (t, J = 7 Hz, 2H); 2.830 (t, J                                     = 6 Hz, 2H); 3.723 (q,                                      N, 8.79 (9.06)                                                                          1565, 1528                                                                            J = 3 Hz, 2H); 3.544 (q, J = 6 Hz, 2H);                                       3.869 (t, J = 7 Hz, 2H);                                    Cl, 7.98 (7.64)   5.656 (q, J =  2 Hz, 1H); 7.15-7.37 (m,                                       4H); 8.626 (brs, 1H)                          I a-46                                                                             2.16-217.5                                                                             C.sub.21 H.sub.25 N.sub.3 O.sub.6 Cl.sub.2.                                             (Nujol) (CDCl.sub.3)                                       (MeOH)   1/5 H.sub.2 O                                                                           3340, 1710, 1645                                                                      1.807 (quint, J = 7 Hz, 2H); 2.027                                            (quint, J = 8 Hz, 2H); 2.48-2.56                   (oxalate)                                                                              C, 51.31 (51.48)                                                                        1588, 1562, 1538                                                                      (m, 4H); 2.599 (t, J = 8 Hz, 2H); 2.689                                       (t, J = 6 Hz, 2H); 3.155 (q,                                H, 5.15 (5.23)                                                                          1488, 1460, 1420                                                                      J = 3 Hz, 2H); 3.383 (q, J = 7 Hz, 2H);                                       3.859 (t, J = 7 Hz, 2H);                                    N, 8.53 (8.58)    6.111 (quint, J = 2 Hz, 1H); 7.20-7.25                                        (m, 3H); 8.510 (brs, 1H)                                    Cl, 14.65 (14.47)                                               I a-47                                                                             99.0-100.0                                                                             C.sub.19 H.sub.24 N.sub.3 O.sub.2 Br;                                                   (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 56.32 (56.16)                                                                        3320, 1712, 1680                                                                      1.819 (quint, J = 7 Hz, 2H); 2.023                                            (quint, J = 7 Hz, 2H); 2.49.2.56                            H, 6.04 (5.95)                                                                          1545, 1489, 1465                                                                      (m, 4H); 2.598 (t, J = 7 Hz, 2H); 2.699                                       (t, J = 6 Hz, 2H); 3.145 (q,                                N, 10.35 (10.34)                                                                        (sh), 1460, 1440                                                                      J = 3 Hz, 2H); 3.386 (q, J = 6 Hz, 2H);                                       3.861 (t, J = 7 Hz, 2H);                                    Br, 19.59 (19.67) 6.064 (quint, J = 2 Hz, 1H); 7.247 (d, J                                      = 8 Hz, 2H); 7.462 (d,                                                        J = 8 Hz, 2H); 8.495 (brs, 1H)                I a-48                                                                             97.5-98.5                                                                              C.sub.19 H.sub.25 N.sub.3 O.sub.2 F:                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 65.89 (66.07)                                                                        3320, 1713, 1682                                                                      1.825 (quint, J = 7 Hz, 2H); 2.021                                            (quint, J - 8 Hz, 2H); 2.49-2.56                            H, 7.03 (7.00)                                                                          1605, 1545, 1510                                                                      (m, 4H); 2.597 (t, J = 8 Hz, 2H); 2.705                                       (t, J = 6 Hz); 3.152 (q,                                    N, 12.07 (12.16)                                                                        1490, 1460                                                                            J = 3 Hz, 2H); 3.389 (q, J = 7 Hz, 2H);                                       3.862 (t, J = 7 Hz, 2H);                                    F, 5.57 (5.50)    5.998 (quint, J = 2 Hz, 1 H); 6.992 (t, J                                     = 8 Hz, 2H); 7.343 (d-d,                                                      J.sub.1 = 8 Hz, J.sub.2 = 5 Hz, 2H);                                          8.495 (brs, 1H)                               I a-49                                                                             136.0-136.5                                                                            C.sub.22 H.sub.26 N.sub.3 O.sub.6 F:                                                    (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 59.13 (59.05)                                                                        3300, 2600(br)                                                                        2.028 (quint, J = 8 Hz, 2H); 2.50-2.60                                        (m, 4H); 2.674 (t, J = 7 hz,                       (maleate)                                                                              H, 5.85 (5.86)                                                                          1720, 1675, 1610                                                                      2H); 2.741 (t, J = 5 Hz, 2H); 3.3216 (q,                                      J = 3 Hz, 2H); 3.551 (q,                                    N, 9.31 (9.39)                                                                          1602, 1570, 1535                                                                      J = 6 Hz, 2H); 3.866 (t, J = 7 Hz, 2H);                                       5.993 (quint, J = 2 Hz, 1H);                                F, 4.48 (4.25)                                                                          1515    6.997 (t, J = 9 Hz, 2H); 7.350 (d-d,                                          J.sub.1 = 9 Hz, J.sub.2 = 5 Hz, 2H);                                          8.615 (brs, 1H)                               I a-50                                                                             185.0-188.0                                                                            C.sub.20 H.sub.23 N.sub.3 O.sub.2 ClF.sub.3.                                            (Nujol) (CDCl.sub.3)                                       (iPrOH--MeOH--                                                                         HCl.1/5 H.sub.2 O                                                                       3320, 2670, 2550                                                                      1.822 (quint, J = 7 Hz, 2H); 2.030                                            (quint, J = 8 Hz, 2H); 2.544                       Et.sub.2 O)                                                                            C, 50.92 (51.11)                                                                        2420, 1710                                                                            (t, J = 8 Hz, 2H); 2.55-2.60 (m, 2H);                                         2.602 (t, J = 8 Hz, 2H);                           (hydrochloride)                                                                        H, 5.15 (5.23)    2.718 (t, J = 5 Hz, 2H); 3.177 (q, J = 2                                      Hz, 2H); 3.393 (q,                                          N, 8.71 (8.94)    J = 7 Hz, 2H); 3.865 (t, J = 7 Hz, 2H);                                       6.10-6.18 (m,                                               Cl, 14.95 (15.08) 1H); 7.40-7.50 (m, 2H); 7.679 (brs, 1H);                                      8.511 (brs, 1H)                                             F, 11.83 (12.12)                                                I a-51                                                                             213.0-215.0                                                                            C.sub.19 H.sub.21 N.sub.3 O.sub.2 ClF.sub.3.                                            (Nujol) (CDCl.sub.3)                                       (iPrOH--MeOH)                                                                          HCl       3500, 2520, 1704                                                                      2.030 (quint, J = 7 Hz, 2H); 2.50-2.60                                        (m, 2H); 2.597 (t, J = 8 Hz,                       (hydrochloride)                                                                        C, 50.38 (50.45)                                                                        1683, 1548, 1493                                                                      2H); 2.678 (t, J = 6 Hz, 2H); 2.777 (t, J                                     = 6 Hz, 2H); 3.236 (q,                                      H, 4.90 (4.90)                                                                          1462    J = 3 Hz, 2H); 3.504 (q, J = 6 Hz, 2H);                                       3.864 (t, J = 7 Hz, 2H);                                    N, 9.22 (9.29)    6.10-6.16 (m, 1H); 7.40-7.50 (m, 2H);                                         7.685 (brs, 1H); 8.625 (brs,                                Cl, 15.65 (15.68) 1H)                                                         F, 12.61 (12.60)                                                I a-52                                                                             83.0-84.0                                                                              C.sub.17 H.sub.22 N.sub.3 O.sub.2 SCl                                                   (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 55.38 (55.50)                                                                        3320, 1712, 1680                                                                      1.801 (quint, J = 7 Hz, 2H); 2.024                                            (quint, J = 7 Hz, 2H); 2.50                                 H, 5.96 (6.03)                                                                          1545    (brs, 2H) 2.520 (t, J = 7 Hz, 2H); 2.596                                      (t, J = 8 Hz, 2H); 2.670 (t,                                N, 11.51 (11.42)  J = 6 Hz, 2H); 3.119 (q, J = 3 Hz, 2H);                                       3.376 (q, J = 7 Hz, 2H);                                    S, 8.69 (8.71)    3.857 (t, J = 7 Hz, 2H); 5.953 (quint, J                                      = 2 Hz, 1H); 6.688 (d,                                      Cl, 9.69 (9.64)   J = 4 Hz, 1H); 6.756 (d, J =  4 Hz, 2H);                                      8.485 (brs, 1H)                               I a-53                                                                             156.4-157.5                                                                            C.sub.21 H.sub.25 N.sub.3 O.sub.6 SCl.sub.2 ;                                           (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 48.58 (48.65)                                                                        3300, 1708, 1680                                                                      1.808 (quint, J = 7 Hz, 2H); 2.030                                            (quint, J = 7 Hz, 2H); 2.48-2.56                   (maleate)                                                                              H, 4.89 (4.86)                                                                          1585, 1535                                                                            (m, 4H); 2.604 (t, J = 8 Hz, 2H); 2.659                                       (t, J = 6 Hz, 2H); 3.136 (q,                                N, 8.02 (8.11)    J = 3 Hz, 2H); 3.383 (q, J = 7 Hz, 2H);                                       3.862 (t, J = 7 Hz, 2H); 5.995                              S, 5.92 (6.18)    (quint, J = 2 Hz, 1H); 6.712 (s, 1H);                                         8.497 (brs, 1H)                               Ia-54                                                                              144.0-145.0                                                                            C.sub.24 H.sub.30 N.sub.3 O.sub.6 Cl                                                    (Nujol) (CDCl.sub.3)                                       (iPrOH)  C, 58.44 (58.59)                                                                        3280, 2400-2280,                                                                      1.78-1.91 (m, 6H); 2.45-2.60 (m, 6H);                                         2.703 (t, J = 6 Hz, 2H); 3.161                     (maleate)                                                                              H, 6.05 (6.15)                                                                          1692, 1650, 1622                                                                      (q, J = 3 Hz, 2H); 3.383 (q, J = 7 Hz,                                        2H); 3.76-3.83 (m, 2H); 6.056                               N, 8.52 (8.54)                                                                          1575, 1522, 1495                                                                      (quint, J = 2Hz, 1H); 7.264, 7.322 (ABq,                                      J = 9 Hz, 4H); 9.449 (brs,                                  Cl, 7.33 (7.21)   1H)                                           I a-55                                                                             134.0-135.5                                                                            C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 62.84 (63.06)                                                                        3280, 1795, 1645                                                                      1.78-1.85 (m, 4H); 2.45-2.60 (m, 4H);                                         2.680 (t, J = 7 Hz, 2H); 2.770                              H, 6.67 (6.68)                                                                          1527, 1495, 1480                                                                      (t, J = 6 Hz, 2H); 3.238 (q, J = 2 Hz,                                        2H); 3.513 (q, J = 7 Hz, 2H);                               N, 11.41 (11.61)                                                                        1463, 1450                                                                            3.80-3.83 (m, 2H); 6.051 (quint, J = 2                                        Hz, 1H); 7.24-7.35 (m, 4H);                                 Cl, 10.05 (9.80)  9.521 (brs, 1H)                               I a-56                                                                             192.5-193.5                                                                            C.sub.24 H.sub.38 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                      (Nujol) (CDCl.sub.3)(free)                                 (CH.sub.2 Cl.sub.2 --                                                                  C, 65.32 (65.51)                                                                        2340, 1916, 1707                                                                      0.966 (d, J = 5 Hz, 3H); 1.314 (s, 9H);                                       1.43-1.57 (m, 3H); 1.67-1.78                       MeOH--iPrOH)                                                                           H, 7.84 (7.90)                                                                          1619, 1563, 1542                                                                      (m, 2H); 1.930 (quint, J = 7 Hz, 2H);                                         2.239 (t, J = 12 Hz, 2H);                          (di-maleate)                                                                           N, 4.77 (4.77)                                                                          1481, 1460, 1446                                                                      2.49-2.58 (m, 2H); 2.528 (t, J = 7 Hz,                                        2H); 2.63-2.74 (m, 4H);                                               1378    3.14-3.21 (m, 4H); 6.027 (quint, J = 1                                        Hz, 1H); 7.330 (ABq,                                                          J = 8 Hz, 4H)                                 I a-57                                                                             191.5-193.0                                                                            C.sub.21 H.sub.32 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                      (Nujol) (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --                                                                  C, 63.75 (63.95)                                                                        2340, 1995, 1709                                                                      0.980 (d, J = 5 Hz, 3H); 1.48-1.66 (m,                                        3H); 1.70-1.82 (m, 2H); 1.953                      MeOH--iPrOH)                                                                           H, 7.31 (7.40)                                                                          1621, 1525(sh),                                                                       (quint, J = 7 Hz, 2H); 2.333 (s, 3H);                                         2.357 (t,                                          (di maleate)                                                                           N, 5.16 (5.14)                                                                          1510(sh), 1483,                                                                       J = 12 Hz, 2H); 2.544 (t, J = 7 Hz, 4H);                                      2.715 (t, J = 8 Hz, 2H);                                              1462, 1449(sh),                                                                       2.78-2.84 (m, 2H); 3.160 (q, J = 3 Hz,                                        2H); 3.298 (d, J = 12 Hz);                                            1379    6.013 (quint, J = 1 Hz, 1H); 7.123, 7.284                                     (ABq, J = 8 Hz, 4H)                           I a-58                                                                             190.0-192.0                                                                            C.sub.23 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                      (Nujol) (CDCl.sub.3)                                       (MeOH--iPrOH)                                                                          C, 64.92 (65.02)                                                                        2360, 1997, 1708                                                                      1.324 (s, 9H); 1.50-2.00 (m, 8H);                                             2.50-2.80 (m, 12H); 3.200 (q, J =                  (di-maleate)                                                                           H, 7.68 (7.74)                                                                          1619, 1570, 1535                                                                      3 Hz, 2H); 6.056 (s, 1H); 7.347 (ABq, J =                                     8 Hz, 4H)                                                   N, 4.91 (4.89)                                                                          1480, 1457, 1448                                                              (sh), 1379                                            I a-59                                                                             193.0-195.0                                                                            C.sub.23 H.sub.37 N.sub.3 .3C.sub.4 H.sub.4 O.sub.4                                     (Nujol) (CDCl.sub.3)                                       (CHCl.sub.3 --                                                                         C, 59.39 (59.58)                                                                        2334, 1995, 1706                                                                      1.313 (s, 9H); 1.786 (quint, J = 7 Hz,                                        2H); 2.296 (s, 3H); 2.37-2.60                      MeOH)    H, 6.95 (7.03)                                                                          1621, 1568, 1542                                                                      (m, 17H); 2.703 (t, J = 5 Hz, 2H); 3.158                                      (q, J = 3 Hz, 2H); 6.028                           (tri-maleate)                                                                          N, 6.01 (5.96)                                                                          (sh), 1478, 1460                                                                      (quint, J = 1 Hz, 1H); 7.382 (ABq, J = 8                                      Hz, 4H)                                                               1439, 1380(sh)                                        I a-60                                                                             75.0-77.0                                                                              C.sub.16 H.sub.21 NO                                                                    (Nujol) (CDCl.sub.3)                                       (Et.sub.2 O--                                                                          C, 77.94 (77.88)                                                                        3110, 3023, 2773                                                                      1.791 (quint, J = 7 Hz, 2H); 2.332 (s,                                        3H); 2.50-2.60 (m, 2H); 2.735                      n-hexane H, 9.16 (9.15)                                                                          1518, 1467, 1412                                                                      (t, J = 6 Hz, 2H); 2.775 (t, J = 6 Hz,                                        2H); 3.221 (q, J = 3 Hz, 2H);                               N, 6.22 (6.05)                                                                          1397, 1379                                                                            3.834 (t, J = 5 Hz, 2H); 6.001 (quint, J                                      = 2 Hz, 1H); 7.123, 7.272                                                     (ABq, J = 8 Hz, 4H)                           I a-61                                                                             115.0-116.0                                                                            C.sub.20 H.sub.39 N.sub.3 O.                                                            (Nujol) (CD.sub.3 OD)                                      (iPrOH--Et.sub.2 O)                                                                    C.sub.4 H.sub.4 O.sub.4                                                                 3405, 2720, 2570                                                                      1.87-12.05 (m, 6H); 2.333 (s, 3H); 2.886                                      (brs, 2H); 3.21-3.36 (m,                           (maleate)                                                                              C, 64.88 (64.99)                                                                        2295, 1642, 1580                                                                      1H); 3.522 (brs, 2H); 3.913 (s, 2H);                                          6.099 (s, 1H; 6.245 (s, 2H);                                H, 7.54 (7.50)                                                                          1538, 1499, 1457                                                                      7.188, 7.369 (ABq, J = 9 Hz, 4 H)                           N, 9.42 (9.47)                                                                          1411, 1380                                            I a-62                                                                             164.0-166.0                                                                            C.sub. 25 H.sub.31 N.sub.3 O.                                                           (Nujol) (CD.sub.3 OD)                                      (MeOH--Et.sub.2 O)                                                                     C.sub.4 H.sub.4 O.sub.4                                                                 3403, 3037, 2330                                                                      1.88-2.06 (m, 4H); 2.951 (brs, 2H);                                           3.20-3.40 (m, 6H); 3.557 (brs,                     (maleate)                                                                              C, 68.89 (68.89)                                                                        1700, 1640, 1578                                                                      2H); 3.959 (brs, 2H); 6.220 (s, 1H);                                          6.248 (s, 2H); 7.30-7.70 (m,                                H, 6.97 (6.98)                                                                          1537, 1498, 1457                                                                      9H)                                                         N, 8.30 (8.31)                                                                          (sh), 1449, 1409                                      I a-63                                                                             150.0-151.5                                                                            C.sub.24 H.sub.28 N.sub.5 OF.sub.3                                                      (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --                                                                  C, 62.55 (62.73)                                                                        1632, 1617(sh),                                                                       1.940 (quint, J = 7 Hz, 2H); 2.450 (t, J                                      = 8 Hz, 2H); 2.547 (t,                             Et.sub.2 O)                                                                            H, 6.08 (6.14)                                                                          1588, 1552, 1495                                                                      J = 7 Hz, 2H); 5.565 (brs, 2H); 2.727 (t,                                     J = 6 Hz, 2H); 6.142 (s,                                    N, 15.13 (15.24)                                                                        1437    1H); 6.515 (t, J = 5 Hz, 1H); 7.448,                                          7.540 (ABq, J = 8 Hz, 4H);                                  F, 12.36 (12.40)  8.301 (d, J = 5 Hz, 2H)                       I a-64                                                                             108.0-109.0                                                                            C.sub.19 H.sub.26 N.sub.2 O                                                             (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (CH.sub.2 Cl.sub.2 --Et.sub.2 O-                                                       C, 76.26 (76.47)                                                                        1625, 1512, 1466                                                                      1.78-2.04 (m, 4H); 2.332 (s, 3H); 2.574                                       (t, J = 8 Hz, 4H); 2.765 (t,                       n-hexane)                                                                              H, 8.70 (8.78)                                                                          1448, 1378                                                                            J = 6 Hz, 2H); 2.881 (t, J = 8 Hz, 2H);                                       3.211 (q, J = 3 Hz, 2H);                                    N, 9.32 (9.39)    3.448 (t, J = 6 Hz, 2H); 3.477 (t, J = 6                                      Hz, 2H); 6.02 (quint,                                                         J = 2 Hz, 1H); 7.122, 7.285 (ABq, J = 8                                       Hz, 4H)                                       I a-65                                                                             183.0-190.0                                                                            C.sub.22 H.sub.31 N.sub.3 O.sub.2.HCl                                                   (Nujol) (CDCl.sub.3)                                       (MeOH--Et.sub.2 O)                                                                     C, 65.06 (65.09)                                                                        3310, 2725, 2670                                                                      1.313 (s, 9H); 2.018 (quint, J = 8 Hz,                                        2H); 2.52-2.64                                     (hydrochloride)                                                                        H, 8.04 (7.95)                                                                          2405, 1709, 1688                                                                      (m, 6H); 2.678 (t, J = 7 Hz, 2H); 2.774                                       (t, J = 6 Hz, 2H);                                          N, 10.38 (10.35)                                                                        1549, 1519, 1488                                                                      3.212, 3.242 (ABq, J = 3 Hz, 2H) 3.545,                                       3.484 (ABq, J =  7 Hz, 2H);                                 Cl, 8.46 (8.73)                                                                         1459, 1430, 1412                                                                      3.859 (t, J = 7 Hz, 2H); 6.029 (quint, J                                      = 2 Hz, 1H); 7.332 (s, 4H);                                           1392    8.604 (brs, 1H)                               I a-66                                                                             216.0--219.0                                                                           C.sub.18 H.sub.21 N.sub.3 O.sub.2 Cl.sub.2.HCl                                          (Nujol) (CDCL.sub.3)                                       (MeOH--Et.sub.2 O)                                                                     C, 51.66 (51.63)                                                                        3290, 2510, 1712                                                                      2.024 (quint, J = 7 Hz, 2H); 2.45-2.55                                        (m, 2H); 2.594 (t, J = 8 Hz,                       (hydrochloride)                                                                        H, 5.34 (5.30)                                                                          1672, 1521                                                                            2H); 2.665 (t, J = 7 Hz, 2H); 2.754 (t, J                                     = 6 Hz, 2H); 3.214 (q,                                      N, 10.01 (10.03)  J = 3 Hz, 2H); 3.497 (q, J = 6 Hz, 2H);                                       3.860 (t, J = 7 Hz, 2H);                                    Cl, 25.12 (25.40) 6.0-6.14 (m, 1H); 7.208 (dd, J.sub.1 = 8                                      Hz, J.sub.2 = 2 Hz, 1H); 7.365 (d,                                            J = 8 Hz, 1H); 7.450 (d, J = 2 Hz, 1H);                                       8.615 (brs, 1H)                               I a-67                                                                             238.0-248.0                                                                            C.sub.19 H.sub.22 N.sub. 3 O.sub.2 F.sub.3.HCl                                          (Nujol) (CDCl.sub.3)                                       (MeOH--Et.sub.2 O)                                                                     C, 54.43 (54.61)                                                                        3310, 2930, 2860                                                                      2.032 (quint, J = 8 Hz, 2H); 2.50-2.66                                        (m, 4H); 2.69 (t, J = 6 Hz,                        (hydrochloride)                                                                        H, 5.59 (5.55)                                                                          2460, 1711, 1687                                                                      2H); 2.722 (t, J = 6 Hz, 2H); 3.256 (q, J                                     = 3 Hz, 2H); 3.518 (q,                                      N, 9.89 (10.06)                                                                         1617, 1541                                                                            J = 6 Hz, 2H); 3.868 (t, J = 7 Hz, 2H);                                       6.14-6.17 (m, 1H); 7.478,                                   Cl, 8.45 (8.48)   7.567 (ABq, J = 9 Hz, 4H); 8.625 (brs,                                        1H)                                                         F, 13.68 (13.64)                                                I a-68                                                                             228.0-232.0                                                                            C.sub.18 H.sub.22 N.sub.3 O.sub.2 Br.HCl                                                (Nujol) (CD.sub.3 OD)                                      (MeOH--Et.sub.2 O)                                                                     C, 50.89 (50.42)                                                                        3320, 2920, 2860                                                                      2.029 (quint, J = 8 Hz, 2H); 2.50-2.60                                        (m, 2H); 2.598 (t, J = 8 Hz,                       (hydrochloride)                                                                        H, 5.58 (5.41)                                                                          2460, 1710, 1685                                                                      2H); 2.675 (t, J = 7 Hz, 2H); 2.769 (t, J                                     = 6 Hz, 2H); 3.216 (q,                                      N, 9.90 (9.80)                                                                          1537    J = 3 Hz, 2H); 3.509 (q, J = 6 Hz, 2H);                                       3.865 (t, J = 7 Hz, 2H);                                    Cl, 8.22 (8.27)   6.04-6.08 (m, 1H); 7.429, 7.247 (ABq, J =                                     9 Hz, 4H); 8.611 (brs, 1H)                    I a-69                                                                             205.0-210.0                                                                            C.sub.24 H.sub.27 N.sub.3 O.sub.2.HCl                                                   (Nujol) (CDCl.sub.3)                                       (MeOH--Et.sub.2 O)                                                                     C, 67.72 (67.67)                                                                        3305, 3045, 2415                                                                      2.205 (quint, J = 8 Hz, 2H); 2.54-2.66                                        (m, 4H); 2.695 (t, J = 7 Hz,                       (hydrochloride)                                                                        H, 6.64 (6.63)                                                                          2405, 1702, 1679                                                                      2H); 2.803 (t, J = 6 Hz, 2H); 3.261 (q, J                                     = 3 Hz, 2H); 3.558, 3.497                                   N, 9.80 (9.87)                                                                          1578, 1540, 1488                                                                      (ABq, J = 7 Hz, 2H); 3.865 (t, J = 7 Hz,                                      2H); 6.128 (quint,                                          Cl, 8.10 (8.32)                                                                         1457, 1444, 1420                                                                      J = 2 Hz, 1H); 7.28-7.67 (m, 9H); 8.624                                       (brs, 1H)                                                             1392                                                  __________________________________________________________________________     *: a solvent for recrystallization                                       

EXAMPLE 72

1-{3-(1-Methyl-2-oxo-imidazolidin-1-yl)propyl}-4-(4-tolyl)-1,2,5,6-tetrahydropyridine(I a-72) ##STR50##

(1) A mixture of 870 mg of the compound (I a-60) and 8.0 ml ofthionylchloride is stirred at room temperature for 2 hours. Afterremoval of the excess reagent under reduced pressure, the residue waswashed with Et₂ O and dried under reduced pressure to prepare 1.067 g(Yield: 99.2%) of the compound (V-3) as pale yellow powder.

IR(CHCl₃) cm⁻¹ : 1600, 1510, 1460, 1410 NMR (CDCl₃): 2.046 (quint, J=7Hz, 2H); 2.334 (s, 3H); 2.54-2.64 (m, 2H); 2.629 (t, J=7H, 2H); 2.723(t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023(quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8 Hz, 4H)

(2) To a solution of 266 mg of 1-methyl-2-oxo-imidazolidine in 5 ml ofDMF was added 115 mg of 60% NaH under ice-cooling. After stirring atroom temperature for 20 minutes, a solution of 553 mg of the compound(V-3) in 4 ml of DMF was added to the reaction mixture and stirred atroom temperature for 90.5 hours. The reaction mixture was concentratedunder reduced pressure and poured into d-HCl. The aqueous layer is madealkaline with NaHCO₃, extracted with CHCl₃ -MeOH (19/1), dried overMgSO₄, and evaporated. The residue is subjected to column chromatographywith silica gel, eluting with CHCl₃ -MeOH (19/1) to prepare 491 mg ofthe compound (I a-72). The maleate is recrystallized from iPrOH-Et₂ O toprepare 439 mg (Yield: 45.8%) of colorless needles. mp. 126.5°-128.0° C.

Anal Calcd. (%) for C₁₉ H₂₇ N₃ O.C₄ H₄ O₄.1/5H₂ O: C, 63.73; H, 7.20; N,9.61 Found: C, 63.78; H, 7.31; N, 9.70 IR (CHCl₃): 2450, 2340, 1910,1689, 1622, 1502, 1451, 1409, 1382 NMR (CDCl₃): 1.797 (quint, J=8 Hz,2H); 2.329 (s, 3H); 2.46-2.62 (m, 4H); 2.712 (t, J=5 Hz, 2H); 2.790 (s,3H); 3.166 (q, J=3 Hz, 2H); 3.255 (t, J=7 Hz, 2H); 3.295 (s, 4H); 6.014(quint, J=2 Hz, 1H); 7.117, 7.283 (ABq, J=8 Hz, 4H)

EXAMPLE 73-91

The compounds (V) obtained in Example 19-21 are reacted in the samemanner as Example 72 to prepare the compound (I a). The reactionconditions are shown in Table 10.

    TABLE 10      ##STR51##           reaction purification product   Ex. No. (V) (VIII) solvent     condition condition mg (Yield) m.p. (°C.) IR                73 (V-3)742 mg      ##STR52##      DMF 5 ml 100° C.47 min. CH.sub.2 Cl.sub.2 /MeOH =      19/1 Ia-73*.sup.1 602 mg (46.2%) 119.0-121.0(iPrOH) (CHCl.sub.3)2455,     2310, 16771622, 1512, 14971464, 1380, 1351      74 (V-2)1.02 g     ##STR53##      DMF 10 ml 100°  C.25 hr. toluene/acetone = 3/1-1/1 Ia-74*.sup.1     266 mg (15.3%) 152.0-154.0(MeOHEt.sub.2 O) (Nujol)2700-1750(br),1695,     1663, 16191532, 1463, 14121378, 1358      75 (V-3)500 mg     ##STR54##      DMF 8 ml 70° C.10 hr. CH.sub.2 Cl.sub.2 /MeOH = 39/1 Ia-75409 mg     (62.4%) 98.0-100.0(CDCl.sub.3MeOH) (CHCl.sub.3)3690, 1771, 16021511,     1488, 14541429, 1416, 1384      76 (V-3)500 mg     ##STR55##      DMF 8 ml 80° C.15 hr. toluene/acetone = 4/1 Ia-76*.sup.1 130 mg     (72.1%) 154.0-155.5(MeOHEt.sub.2 O) (Nujol)3050, 2660, 26152570, 2480,     24101606, 1590, 15781517, 1498, 14791447, 1423, 13981376  77 (V-3)650 mg      ##STR56##      DMF 6 ml 100° C.5 hr. toluene/acetone = 9/1 Ia-77*.sup.1 1.08 g     (71.4%) 174.0-176.0 (dec.)(MeOHEt.sub.2 O) (CHCl.sub.3)3685, 3495,     33502700-1800(br),1778, 1707, 16211511, 1496, 14461395      ##STR57##      78 (V-2)440 mg     ##STR58##      DMF 8 ml 110° C.6 hr. 20 min. toluene/acetone = 9/1 Ia-78*.sup.1 1     35 mg (17.6%) 149.0-151.0(MeOHEt.sub.2 O) (CHCl.sub.3)3575, 3338  79     (V-3) NaOPh 207 mg DMF 8 ml 70° C. toluene/acetone =  9/1     Ia-79*.sup.1 148.0-150.0 (Nujol)  0.828 g   3 hr. 10 min.  562 mg     (66.3%) (MeOHEt.sub.2 O-iPrOH) 2720, 2370, 1701         1620, 1598, 1584             1499, 1467,         1458(sh), 1387      80 (V-3)942 mg     ##STR59##      -- 150° C.8 hr. 15 min. toluene/acetone = 19/1-9/1 Ia-80*.sup.1     930 mg (54.4%) 148.0-150.0(iPrOHEt.sub.2      O) (Nujol)2720, 2575(sh),2490(sh), 2330,1708, 1652, 16001571, 1502,     1459      81 (V-3)624 mg     ##STR60##      -- 150° C.4 hr. 10 min. CH.sub.2 Cl.sub.2 /MeOH =      19/1 Ia-81*.sup.1 963 mg (66.6%) 191.0-192.0 (dec.)(MeOHEt.sub.2 O)     (Nujol)3030, 2720, 22781711, 1623, 15721532, 1513(sh),1485, 1463, 1435     82 (V-3) HN(iBu).sub.2 1.358 g -- 20 hr. CH.sub.2 Cl.sub.2 /MeOH = 49/1     Ia-82*.sup.1 140.5-142.5 (Nujol)  517 mg   reflux  457 mg (38.4%)     (CH.sub.2 Cl.sub.2Et.sub.2 O) 2710, 2500, 1706         1572, 1480, 1455            1375 83 (V-3) H.sub.2 N(iBu) 1.02 ml -- 10.5 hr. CH.sub.2     Cl.sub.2 /MeOH/NH.sub.4 OH = 128/12/1 Ia-83*.sup.1 179.5-182.5 (Nujol)     511 mg   reflux  471 mg (44.4%) (CH.sub.2 Cl.sub.2Et.sub.2 O) 3340,     2780, 2545         2460, 1699, 1618         1577, 1474, 1458     1441, 1381      84 (V-3)466 mg     ##STR61##      -- 50° C.3 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH =      128/16/1-32/4/0.5 Ia-84*.sup.1 225 mg (42.4%) 180.0-181.0 (Nujol)2340,     1709, 15501458, 1377, 156  85 (V-3) H.sub.2 N(CH.sub.2).sub.2      N(iPr).sub.2 -- 105° C. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH =     128/16/1-64/8/1 Ia-85*.sup.1 125.0-127.0 (Nujol)  511 mg 1.054 g  7 hr.     436 mg (32.0%)  2668, 2500, 2400         (sh), 1702, 1619         1570,     1462, 1378 86 (V-2) HN(iBu).sub.2 1.50 g -- 32 hr. CH.sub.2 Cl.sub.2     /MeOH = 49/1-19/1 Ia-86*.sup.1 135.0-136.5 (Nujol)  654 mg   reflux  338     mg (27.1%)  2420, 1707, 1616         1572, 1485, 1456         1377 87     (V-2) HN(iBu).sub.2 1.1 ml -- 32 hr. CH.sub.2 Cl.sub.2 /MeOH = 49/1-19/1     Ia-87*.sup.1 135.0-136.0 (Nujol)  645 mg   reflux  338 mg (27.1%)     (MeOHEt.sub.2 O) 2420, 1707, 1616         1572, 1485, 1456         1377     88 (V-2)1.05 g      ##STR62##      -- roomtemperature32.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH =     128/16/1-32/4/0.5 Ia-88*.sup.1 1.034 g (52.4%) 176.0-178.0(MeOH)     (Nujol)3483, 2723, 26792587, 2415, 17031608, 1579, 14781460, 1412, 1382     89 (V-2)621 mg      ##STR63##      -- roomtemperature5 days CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 128/16/1 I     a-89*.sup.1 800 mg (67.3%) 190.0-191.0 (dec.)(MeOH) (Nujol)2355, 1711,     16201577, 1543, 1479(sh), 1461, 1378      90 (V-1)828 mg     ##STR64##      -- 150° C.3 hr. CH.sub.2 Cl.sub.2 /MeOH = 29/1-19/1 Ia-90*.sup.1 1     .025 g (58.0%) 183.5-185.0(CHCl.sub.3MeOH) (Nujol)2340, 1708, 16191568,     1528(sh),1485, 1461  91 (V-1) HN(iBu).sub.2 3.76 ml -- 33 hr. CH.sub.2     Cl.sub.2 /MeOH = 49/1-19/1 Ia-91*.sup.1 176.5-178.0 (dec.) (Nujol)  628     mg   reflux  685 mg (51.6%) (MeOHEt.sub.2 O) 2620, 2510, 1690     1657, 1618, 1579         1533, 1488, 1460         1409, 1378     *.sup.1 : maleate

EXAMPLE 92

4-(4-tert-Butylphenyl)-1-[3-{4-(pyrimidin-2-yl)piperazin-1-yl}propyl]-1,2,5,6-tetrahydropyridine(I a-92) ##STR65##

(1) A mixture of 1.1 g of3-{4-(pyrimidin-2-yl)piperazin-1-yl}propylchloride, 1.07 g of thecompound (II-6), 1.26 g of K₂ CO₃, and 1.03 g of NaI in 12 ml of DMF isstirred at 100° C. for 4 hours. The reaction mixture is poured intoice-water and extracted with ethyl acetate. The organic layer is washedwith water, dried and evaporated. The residue is purified by silica gelchromatography (CH₂ Cl₂ /MeOH=10/1) followed by recrystallization fromCH₂ Cl₂ -Et₂ O to prepare 1.70 g (Yield: 85%) of the compound (III-56).mp. 215.0°-225.0° C. (dec.)

(2) A solution of 1.58 g of the compound (III-56) in 15 ml of CF₃ COOHis refluxed for 3.5 hours. After removal of the excess reagent, theresidue is poured into ice-cooled aq.NaHCO₃ and extracted. The organiclayer is dried over Na₂ SO₄ and evaporated under reduced pressure. Theoily residue is purified by column chromatography with silica gel,eluting wit CH₂ Cl₂ /MeOH (10/1-5/1) to prepare 1.44 g (Yield: 95%) ofthe compound (I a-92) as crystals (mp. 79.O°-81.0° C.). The maleate isrecrystallized from methanol to prepare colorless needles. mp.209.0°-211.0° C. (dec.)

EXAMPLE 93-94

The reactions are performed in the same manner as Example 92 to preparethe compound (III) and (I a). The reaction conditions and physicalconstants are shown in Tables 11 and 12.

                                      TABLE 11                                    __________________________________________________________________________    (Step 1)                                                                       ##STR66##                                                                    Ex.                 DMF K.sub.2 CO.sub.3                                                                  NaI                                                                              reaction                                                                             purification                                                                            g(Yield)                      No.                                                                              (II)                                                                              R(CH.sub.2).sub.n Y (VI)                                                                   (ml)                                                                              (g) (g)                                                                              condition (1)                                                                        condition (1)                                                                           Compd. No                                                                           m.p.                    __________________________________________________________________________                                                          (°C.)            93 (II-6) 980 mg                                                                      ##STR67##   20  1.16                                                                              0.94                                                                             105 6.5 hr.                                                                          CH.sub.2 Cl.sub. 2 /MeOH                                                                1.69 (92.6) (III-57)                                                                129.0-130.5                                                                   (CH.sub.2 Cl.sub.2                                                            Et.sub.2 O)                                                                   (maleate)               94 (II-6) 2.67 g                                                                      ##STR68##   20  3.18                                                                              2.60                                                                             95-100 17 hr.                                                                        CH.sub.2 Cl.sub.2 /MeOH                                                                 4.04 (93.3) (III-58)                                                                137.0-138.5                                                                   (CH.sub.2 Cl.sub.2                                                            Et.sub.2 O)                                                                   (maleate)               __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________    Step 2                                                                        (III)            purification                                                                              (I a)                                            (g)  CF.sub.3 COOH                                                                       reflux time                                                                         condition   g(Yield)                                                                           m.p. (°C.)                                                                   IR                                    __________________________________________________________________________    (III -57)                                                                          20 ml 4 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                 I a-93                                                                             105-106                                                                             (Nujol)                               1.50 g           20/1-10/1   1.40 g                                                                             (MeOH)                                                                              1710, 1622, 1598, 1575,                                            (97.4)     1495 (sh), 1480, 1462,                                                        1450, 1385, 1360                      (III -58)                                                                          10 ml 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                            I a-94                                                                             213.0-214.5                                                                         (Nujol)                               0.88 g                       maleate                                                                            (MeOH)                                                                              2300, 1717, 1622, 1575,                                            0.74 g     1535, 1500, 1465, 1458,                                            (97.5)     1450                                  __________________________________________________________________________

EXAMPLE 95

4-(4-Hydroxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropryridine(I a -95) ##STR69##

(1) A mixture of 2.829 g of 4-(4-methoxyphenyl)-4-hydroxypiperidine,2.02 ml of 3-bromopropylchloride, and 3.773 g of K₂ CO₃ in 30 ml of DMFis stirred at room temperature for 3 hours. The reaction mixture ispoured into ice-water and extracted with ethyl acetate. The organiclayer is dried and evaporated under reduced pressure to prepare 4:525 gof pale yellow solid. Purification is conducted by column chromatographywith silica gel, eluting with CH₂ Cl₂ /MeOH (29/1-5/1) to prepare 3.316g (Yield: 85.6%) of the compound (IV-8) as solid which is recrystallizedfrom n-hexane-Et₂ O to prepare colorless needles. mp. 103.5°-105.0° C.

Anal Calcd. (%) for C₁₅ H₂₂ ClNO₂ : C,63.48; H,7.81; N,4.94; Cl,12.49Found: C,63.47; H,7.78; N,5.01; Cl,12.45 IR(CHCl₃): 3595, 1610, 1582,1510, 1468, 1462, 1454, 1441, 1375 NMR (CDCl₃) δ: 1.761 (d-d, J₁ =14 Hz,J₂ =3 Hz, 2H); 1.998 (quint, J=7 Hz, 2H); 2.121 (t-d, J₁ =13 Hz, J₂ =4Hz, 2H); 2.475 (t-d, J₁ =12 Hz, J=3 Hz, 2H); 2.560 (t, J=7 Hz, 2H);2.782 (d-d, J₁ =14 Hz, J₂ =3 Hz, 2H); 3.618 (t, J=7 Hz, 2H); 3.805 (s,3H); 6.886, 7.427 (ABq, J=9 Hz, 4H)

(2) To a solution of 3.176 g of the compound (IV-8) is added 3.17 ml ofBBrs with stirring under ice-cooling. After refluxing for 1.5 hours, thereaction mixture is poured into ice-water and the aqueous layer is madealkaline with c.NH₄ OH and extracted with CH₂ Cl₂ /MeOH (4/1). Theorganic layer is dried and evaporated to dryness. The crude product isdissolved in 20 ml of CF₃ COOH and refluxed for 1 hour, The reactionmixture is concentrated under reduced pressure and poured intoice-water. The aqueous layer is made alkaline with c.NH₄ OH andextracted with CH₂ Cl₂ /MeOH (4/1). The organic layer is dried andevaporated to prepare 1.701 g (Yield 57.2%) of the compound (V-6) assolid, which is recrystallized from MeOH-n-hexane to prepare thecompound (V-6) as pale orange plates. mp. 208.0°-200° C.

Anal Calcd. (%) for C₁₄ H₁₈ ClNO: C,66.79; H,7.21; N,5.56; Cl,14.08Found C,66.79; H,7.26; N,5.52; Cl,14.25 IR(Nujol): 3025, 2773, 2650,2560, 1607, 1578, 1515, 1453, 1429, 1382 NMR (CDCl₃ CD₃ OD) δ: 2.66(quint, J=8 Hz, 2H); 2.47-2.76 (m, 4H); 2.774 (t, J=6 Hz, 2H); 3.200 (q,J=2 Hz, 2H); 3.637 (t, J=6 Hz, 2H); 5.972 (s, 1H); 6.803, 7.275 (ABq,J=9 Hz, 4H)

(3) A stirred mixture of 1.482 g of the compound (V-6) and 2.57 ml ofmorpholine is refluxed for 2 hr. 15 min. After removal of the reagent,the residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH/NH₄ OH (128/16/1-64/8/1) to give 1.047 g(Yield: 58.8%) of the compound (I a-95) as a solid. The maleate isrecrystallized from MeOH-Et₂ O to prepare pale yellow plates. mp.166.0°-167.5° C. (d.)

Anal Calcd. (%) for C₁₈ H₂₆ N₂ O₂.2C₄ H₄ O₄ : C,58.22; H,6.48; N,5.35Found: C,58.42; H,6.41; N,5.24 IR (Nujol): 3230, 3063, 2725, 2355, 1715,1625, 1579, 1519, 1464, 1387 NMR (CD₃ OD) δ: 2.13-2.35 (m, 2H); 2.866(brs, 2H); 3.03-3.25 (m, 6H) 3.25-3.40 (m, 2H); 3.564 (t, J=6 Hz, 3H);3.883 (t, J=5 Hz, 4H); 3.953 (brs, 2H); 5.999 (brs, 1H); 6.264 (s, 4H);6.778, 7.320 (ABq, J=9 Hz, 4H)

EXAMPLE 96

4-(4-Hydroxyphenyl)-1-{3-(1-pyrrolidinyl)propyl}-1,2,5,6-tetrahydropyridine(I a-96) ##STR70##

A mixture of 1.50 g of the compound (V-6) and 4.97 ml of pyrrolidine isstirred at room temperature for 18.5 hours and treated in the samemanner as Example 95 (3) to prepare 2.041 g (Yield: 66.1%) of themaleate of the compound (I a-96) as needles. mp. 145.0°-147.0° C. (dec.)

Anal Calcd. (%) for C₁₈ H₂₅ N₂ O.2C₄ H₄ O₄₄ : C, 60.03; H, 6.42; N, 5.50Found: C, 60.22; H, 6.61; N, 5.40 IR (Nujol): 3230, 3041, 2710(sh),2590, 2360, 1709, 1622, 1578, 1518, 1461, 1377 NMR (CD₃ OD): 2.00-2.175(m, 4H); 2.175-2.375 (m, 2H); 2.859 (brs, 2H); 3.23-3.48 (m, 8H); 3.542(t, J=6 Hz, 3H); 3.992 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.778,7.320 (ABq, J=8 Hz, 4H)

EXAMPLE 97

1-{3-(N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(I a-97) ##STR71##

A mixture of 3.00 g of the compound (V-6) and 11.84 ml of BuNH₂ isrefluxed for 5 hours, and treated in the same manner as Example 96 toprepare 2.188 g (Yield: 63.7%) of the compound (I a-97) as needles. mp.233.0°-236.0° C. (dec.) IR (Nujol): 3425, 3055, 2778, 2670, 2582, 1655,1613, 1590, 1515, 1471, 1453, 1439, 1428 NMR (CDCl₃): 0.920 (d, J=7 Hz,6H); 1.92-2.18 (m, 3H); 2.554 (brs, 2H); 2.692 (d, J=7 Hz, 2H); 2.751(t, J=6 Hz, 2H); 2.854 (t, 2H); 2.854 (t, J=6 Hz, 2H); 3.134 (t, J=6 Hz,2H); 3.247 (brs, 2H); 5.922 (brs, 1H ); 6.818, 7.194 (ABq, J=9 Hz, 4H)

EXAMPLE 98

1-{3-(N-isobutyl-N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(I a-98) ##STR72##

Treatment of 2.138 g of the compound (I a-97) in the same manner asExample 34 prepares 1.528 g (Yield: 70.1%) of the compound (I a-98) assolid, which is crystallized as maleate and recrystallized from MeOH-Et₂O to prepare pale yellow plates. mp. 150.0°-153.0° C. (dec.)

Anal Calcd. (%) for C₁₉ H₃₀ N₂ O.2C₄ H₄ O₄ : C, 60.38; H, 7.16; N, 5.38Found: C, 60.66; H, 7.16; N, 5.24 IR (Nujol): 3235, 2700(sh), 2400,1618, 1576, 1517, 1459, 1380 (sh), 1372(sh), 1359 NMR (CD₃ OD) δ: 1.051(d, J=7 Hz, 6H); 2.025-2.400 (m, 3H); 2.852 (brs, 2H); 2.916 (s, 3H);3.026 (d, J=7 Hz, 2H); 3.15-3.38 (m, 4H); 3.533 (t, J=6 Hz, 2H); 3.917(brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.777,7.318 (ABq, J=9 Hz, 4H)

EXAMPLE 99

4-(4-Methoxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine(I a-99) ##STR73##

A stirred mixture of 1.147 g of the compound (IV-8) and 1.76 ml ofmorpholine is refluxed for 1 hour. After removal of the reagent, theresidue is purified by silica gel column chromatography (CH₂ Cl₂/MeOH/NH₄ OH=64/8/1-32/6/1) to prepare 1.34 g of the compound (III-59)as oily substance. The oily product is dissolved in 10 ml of CF₃ COOHand refluxed for 1 hour. After removal of the reagent, the residue ispoured into aq. NH₄ OH and extracted with methylene chloride. Theorganic layer is dried and evaporated under reduced pressure to prepare1.012 g of the oily product. The oily product is subjected to columnchromatograpy with silica gel, eluting with CH₂ Cl₂ /MeOH(19/1). Theeluate is recrystallized from Et₂ O-n-hexane to prepare of 637 mg(Yield: 50.2%) of the compound (I a-9) as colorless needles. mp.69.0°-70.5° C.

Anal Calcd. (%) for C₁₉ H₂₈ N₂ O₂ : C, 72.12; H, 8.92; N, 8.85 Found: C,72.01; H, 8.88; N, 9.05 IR (CHCl₃): 2490, 1610, 1572, 1512, 1466, 1446,1417, 1402, 1378 NMR (CHCl₃) δ: 1.779 (quint, J=7 Hz, 2H); 2.33-2.63 (m,10H); 2.706 (t, J=5 Hz, 2H); 3.151 (q, J=4 Hz, 2H); 3.725 (t, J=5 Hz,4H); 3.802 (s, 3H); 5.969 (quint, J=2 Hz, 1H); 6.851, 7.322 (ABq, J=9Hz, 4H)

EXAMPLE 100

4-(4-tert-Butylphenyl)-1-{3-(2,6-dimethylmorpholino)propyl}-1,2,5,6-tetrahydropyridine(I a-100) ##STR74##

(1) A mixture of 1.150 g of the compound (IV-2) and 2.29 ml of cis2,6-dimethylmorpholine is stirred at 103°-135° C. for 4 hours. Afterremoval of the reagent, the residue is poured into aq.NaOH and extractedwith methylene chloride. The organic layer is dried and evaporated underreduced pressure. The residue is purified by column chromatography withsilica gel, eluting with CH₂ Cl₂ -MeOH (15/1-5/1) to prepare 1.37 g(Yield: 95.0%) of the compound (III-60) as crystals. mp. 137.5°-138.0°C. (dec.) IR (CHCl₃): 3610, 3010, 2970, 2870, 2820, 1780, 1605, 1512cm⁻¹ NMR (CDCl₃) δ: 1.161 (d, J=6 Hz, 6H); 1.319 (s, 9H); 1.63-1.88 (m,7H); 2.215 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.30-2.60 (m, 6H); 2.753 (dd,J.sub. 1 =12 Hz, J₂ =2 Hz, 2H); 2.875 (dd, J₁ =11 Hz, J₂ =2 Hz, 2H);3.60-3.75 (m, 2H); 7.377,7.451 (ABq, J=9 Hz, 4H)

(2) A solution of 1.35 g of the compound (III-60) in 10 ml of CF₃ COOHis refluxed for 4 hour. After removal of the reagent, the residue ispoured into aq.NaHCO₃ and extracted with ethyl acetate. The organiclayer is washed with water, dried and evaporated under reduced pressure.The oily residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH (25/1-15/1) to prepare 1.29 g (Yield: 86.8%)of the compound (I a-100) as an oil. The maleate is recrystallized fromMeOH-iPrOH to prepare colorlees needles. mp. 192.0°-193.0° C.

Anal Calcd. (%) for C₂₄ H₃₈ N₂ O.2C₄ H₄ O₄ : C, 63.58; H, 7.79; N, 4.64Found: C, 63.77; H, 7.69; N, 4.65 IR (Nujol): 1707, 1618 cm⁻¹ NMR(CDCl₃): 1.260 (d, J=7 Hz, 6H); 1.330 (s, 9H); 2.20-2.40 (m, 2H); 2.491(t, J=12 Hz, 2H); 2.80-2.95 (m, 2H); 3.111 (t, J=8 Hz, 2H); 3.28-3.40(m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 3.542 (t, J=6 Hz,2H); 3.80-4.00 (m, 4H); 6.02-6.08 (m, 1H); 6.283 (s, 2H); 7.355,7.422(ABq, J=9 Hz, 4H)

EXAMPLE 101-104

The reaction is performed in the same manner as Example 100 to preparethe compound (I a). The reaction conditions are shown in Tables 13 and14.

                                      TABLE 13                                    __________________________________________________________________________     ##STR75##                                                                     ##STR76##                                                                    Ex.                   reaction                                                                            purification product                              No.                                                                              (IV) (XI)      solvent                                                                           condition                                                                           condition    g (Yield)                                                                          m.p. (°C.)                                                                   IR                        __________________________________________________________________________    101                                                                              X = Me                                                                             Z = O, R = H                                                                             -- 2 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                  III-61                                                                             103.0-104.5                                                                         (CHCl.sub.3)                 3.55 g                                                                             5.77 g        reflux                                                                              15/1-5/1     4.23 g     3600, 3020, 2950,                                                             2920,                                                              (96.0%)    2820, 1513, 1472          102                                                                              X = Cl                                                                             Z = O, R = H                                                                            --  130-135° C.                                                                  --           III-62                                                                             236.0-237.0                                                                         (Nujol)                      5.1 g                                                                              7.71 g        2.5 hr.            5.97 g     3440, 2930, 2870,                                                             2640,                                                              (99.5%)    2550, 2460                103                                                                              X = t-Bu                                                                           Z = NH, R = Me                                                                          DMF 95-100° C.                                                                   CH.sub.2 Cl/MeOH/NH.sub.4 OH                                                               III-63                                                                             --    (CHCl.sub.3)                 2.35 g                                                                             1.73 g    20 ml                                                                             2 hr. 30/6/1       1.92 g     3000, 3330, 2960,                                                             2820,                                                              (65.3%)    2470, 1665, 1635,                                                             1605,                                                                         1590, 1510                104                                                                              X = Cl                                                                             Z = NH, R = Me                                                                          DMF 80-85° C.                                                                    CH.sub.2 Cl/MeOH/NH.sub.4 OH                                                               III-64                                                                             --    (CHCl.sub.3 )                2.05 g                                                                             1.62 g    15 ml                                                                             3.5 hr.                                                                             32/6/1       2.10 g     3590, 3160, 2930,                                                             2810,                                                              (80.9%)    2490, 1677, 1596,         __________________________________________________________________________                                                        1492                  

                                      TABLE 14                                    __________________________________________________________________________                             purification                                                                             product                                   Ex. No.                                                                            (III)                                                                              CF.sub.3 COOH                                                                       reaction condition                                                                     condition  g (Yield)                                                                          m.p. (°C.)                                                                     IR                           __________________________________________________________________________    101  (III -61)                                                                          45 ml 2.5 hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                I a-101                                                                            186.5-188.5*.sup.1                                                                    (Nujol)                           4.45 g     reflux   15/1-5/1   3.99 g       1709, 1621                                                       (92.0%)                                   102  (III -62)                                                                          45 ml 7 hr.    CH.sub.2 Cl.sub.2 /MeOH =                                                                I a-102                                                                            185.5-186.5*.sup.1                                                                    (Nujol)                           3.78 g     reflux   15/1-5/11  3.00 g       2300 (br), 1709, 1622                                            (84.2%)                                   103  (III -63)                                                                          20 ml room     CH.sub.2 Cl.sub.2 /MeOH/                                                                 I a-103                                                                            235.0-250.0*.sup.2                                                                    (Nujol)                           1.92 g     temperature                                                                            NH.sub.4 OH =                                                                            1.60 g       3440, 3410, 2670, 2580,                                                       2470                                         2.5 hr. reflux                                                                         128/16/1   (87.4%)      2420, 1658, 1555, 1507       104  (III -64)                                                                          25 ml room     CH.sub.2 Cl.sub.2 /MeOH/                                                                 I a-104                                                                            179.0-181.0*.sup.2                                                                    (Nujol)                           2.10 g     temperature                                                                            NH.sub.4 OH =                                                                            1.79 g       3600, 2680, 2530, 2440,                                                       1642                                         15 hr. reflux                                                                          128/16/1   (89.6%)      1597, 1496                   __________________________________________________________________________     *.sup.1 : maleate                                                             *.sup.2 : hydrochloride                                                  

EXAMPLE 105

1-[3-{4-(3,4-Dimethoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine(I a-105) ##STR77##

To a solution of 3.76 g of4-(3,4-dimethoxyphenyl)1,2,5,6-tetrahydropyridine (V-7), which wasprepared by the reaction of 4-hydroxy-4-(3,4-dimethoxyphenyl)piperidineand p-toluenesuifonic acid, and 2.94 g of1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine in 35 ml of DMF is added3.98 g of K₂ CO₃ and 3.22 g of NaI. The reaction mixture is stirred at100°-105° C. for 6 days under nitrogen gas. After cooling to roomtemperature, the mixture is diluted with ethyl acetate, washed withbrine and dried over MgSO₄. After removal of the solvent, the residue issubjected to column chromatography with silica gel, eluting with CH₂ Cl₂/MeOH (20/1) to prepare 1.78 g (Yield: 33.4%) of the compound (I a-105)as solid. The oxalate is recrystallized from iPrOH-MeOH to prepareneedles. mp. 178.0°-182.0° C.

Anal Calcd. (%) for C₂₃ H₃₁ N₃ O₈.1/5H₂ O: C, 57.35; H, 6.33; N, 8.67Found: C, 57.42; H, 6.58; N, 8.73 IR (Nujol): 3310, 1725(sh), 1708,1682, 1675, 1600, 1580, 1545, 1545, 1520 NMR (CDCl): 1.764 (quint, J=7Hz, 2H); 1.954 (quint, J=8 Hz, 2H); 2.44-2.51 (m, 4H); 2.530 (t, J=8 Hz,2H); 2.646 (t, J=5 Hz, 2H); 3.094 (q, J=3 Hz, 2H); 3.328 (q, J=7 Hz,2H); 3.795 (t, J=7 Hz, 2H); 3.809, 3.827 (sx2, 6H); 5.915 (quint, J=3Hz, 1H); 6.755 (d, J=9 Hz, 2H); 6.84-6.89 (m, 2H); 8.434 (brs, 1H)

EXAMPLE 106

1-[3-{4-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine(I a-106) ##STR78##

The compound (V-8) is reacted in the same manner as Example 105 toprepare the compound (I a-106). mp. 199.5°-200.0° C. (dec.)

Anal Calcd. (%) for C₂₂ H₂₉ N₃ O₇ : C, 58.81; H, 6.31; N,9.32 Found: C,59.02; H, 6.53; N, 9.39 IR (Nujol): 3300, 2730, 2620, 1700, 1685, 1612,1548, 1529, 1465 NMR (CDCl₃): 1.90-2.10 (m, 4H); 2.590 (t, J=7 Hz, 2H);2.80-2.86 (m, 2H) 3.23-3.30 (m, 2H) 3.33-3.52 (m, 4H); 3.778 (s, 3H);3.898 (m, 2H); 5.995 (s, 1H); 6.893, 7.379 (ABq, J=8 Hz, 4H)

EXAMPLE 107

1-[4-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}butylcarbamoyl]-2-oxopyrrolidine(I a-107) ##STR79##

(1) To a solution of 4.00 g of the compound (II-8) and 4.675 g ofN-Boc-β-alanine in 90 ml of THF are added 5.178 g of1,3-dicyclohexylcarbodiimide and 848 mg of 1-hydroxybenzotriazolehydrate. The reaction mixture is stirred at room temperature for 2 hoursand 10 minutes. After removal of precipitates, the reaction mixture isconcentrated under reduced pressure. The residue is poured into d.HCland extracted with CH₂ Cl₂. The organic layer is washed with aq.NaHCO₃and water in order, dried over MgSO₄ and evaporated under reducedpressure. The residue is subjected to column chromatography with silicagel, eluting with toluene/acetone (3/1-2/1) to prepare 6.862 g ofcrystalline residue. It is recrystallized from methylenechloride-ether-n-hexane to prepare 6.674 g (Yield: 84.8%) of thecompound (IV-9) as colorless needles. mp. 161.5°-163.0° C.

Anal calcd. (%) for C₂₁ H₃₂ N₂ O₄ : C, 67.18; H, 8.46; N, 7.50 Found: C,66.99; H, 8.57; N, 7.44 IR (CHCl₃): 3957, 3457, 1709, 1628, 1508, 1474,1448, 1393, 1369 NMR (CDCl₃) δ: 1.432 (s, 9H); 1.75,2.05 (m, 8H); 2.344(s, 3H); 2.147 (t, J=7 Hz. 2H); 3.04,3.20 (m, 3H); 3.560 (td, J₁ =12 HzJ₂ =4 Hz, 1H); 3.737 (d, J=14 Hz, 1H); 4.548 (d, J=13 Hz, 1H); 4.833(brs, 1H); 7.177,7.353 (ABq, J=8 Hz, 4H)

(2) A solution of 6.654 g of the compound (IV-9) in 13 ml of CF₃ COOH isstirred at room temperature for 2.5 hours. After removal of the excessreagent, 6.36 g of the crystalline residue is obtained. The residue isrecrystallized from MeOH-Et₂ O to prepare 5.798 g of colorless plates.Then to a solution of 4.818 g of the plates in 30 ml of methanol isadded 5 ml of triethylamine. After removal of the solvent to dryness,the resulting solid is dropwise added to a stirred suspension of 737 mgof LiAlH₄ in 80 ml of THF at room temperature and stirred at the sametemperature for 2.5 hours. After decomposition of the excess reagent bycareful addition of water, the resulting precipitate is filtered off.The organic layer is evaporated to dryness to prepare 3.612 g of theyellow oily residue. The residue is subjected to column chromatographywith silica gel, eluting with CHCl₃ /MeOH/c.NH₄ OH (32/4/0.5-32/6/1) toprepare 1.341 g (Yield: 42.4%) of the compound (V-9).

(3) A mixture of 1.341 g of the compound (V-9) and 1.126 g of1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 1 hour 43minutes. The reaction mixture is purified by column chromatography withsilica gel, eluting with toluene/acetone (2/1-1/1) followed byrecrystallization from Et₂ -n-hexane to prepare 540 mg (Yield: 24.7%) ofthe compound (I a-107) as prisms. mp. 104.0°-104.5° C.

Anal Calcd. (%) for C₂₁ H₂₉ N₃ O₂ : C, 71.05; H, 8.22; N, 11.84 Found:C, 70.95; H, 8.22; N, 11.82 IR (CHCl₃): 3325, 1714, 1682, 1602, 1548,1516, 1490, 1461, 1442, 1387 NMR (CDCl₃) δ:1.62,1.66 (m, 4H); 2.025(quint, J=7 Hz, 2H); 2.330 (s, 3H); 2.30-2.73 (m, 8H); 3.145 (q, J=3 Hz,2H); 3.338 (q, J=6 Hz, 2H); 3.858 (t, J=7 Hz, 2H); 6.016 (quint, J=2 Hz,1H); 7.117, 7.283 (ABq, J=8 Hz, 4H); 8.430 (brs, 1H)

EXAMPLE 108

1-[{5-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}pentylcarbamoyl]-2-oxopyrroridine(I a-108) ##STR80##

A mixture of 4.675 g of BocNH(CH₂)₄ COOH and 4.00 g of the compound(II-8) is treated in the same manner as Example 107 (1)-(3) to prepare392 mg (Yield: 15.0%) of the compound (I a-108). mp. 58.5°-59° C.

Anal Calcd. (%) for C₂₂ H₃₁ N₃ O₂ : C, 71.23; H, 8.42; N, 11.46 Found:C, 71.51; H, 8.46; N, 11.37 IR (CHCl₃): 3321, 1714, 1681, 1548, 1516,1489 1461, 1387 NMR (CDCl₃ -CD₃ OD) δ:1.32-1.45 (m, 2H); 1.52-1.70 (m,4H); 2.039 (quint, J=7 Hz, 2H); 2.333 (s, 3H); 2.429-2.507 (m, 2H);2.615 (t, J=8 Hz, 4H); 2.723 (t, J=6 Hz, 2H); 3.161 (q, J=3 Hz, 2H);3.303 (q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 6.032 (s, 1H); 7.126,7.292 (ABq, J=8 Hz, 4H); 8.460 (brs, 1H)

EXAMPLE 109

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(I a-109) ##STR81##

(1) A mixture of 3.6 g of 3-(3,4-dichlorophenoxy)propylchloride, whichwas prepared by the reaction of 3,4-dichorophenol with3-bromopropylchloride, and 3.12 g of4-hydroxy-4-(4-methoxyphenyl)piperidine, 4.15 g of K₂ CO₃, and 3.37 g ofNaI in 35 ml of DMF is stirred at 105° C. for 10 hour. The reactionmixture is poured into ice-water, and the resulting precipitates areextracted with methylene chloride. The organic layer is dried andevaporated under reduced pressure. The residue is purified by columnchromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (20/1-10/1)followed by recrystallization from methylene chloride to prepare 5.86 g(Yield: 95.2%) of the compound (III-65) as colorless needles. mp.131.0°-132.0° C.

Anal Calcd. (%) for C₂₁ H₂₅ N₂ O₃ Cl₂ : C, 61.39; H, 6.20; N, 3.55; Cl,17.28 Found: C, 61.47; H, 6.14; N, 3.41; Cl, 17.30 IR (CHCl₃): 3600,1612, 1595, 1568, 1513, 1480(sh), 1468 NMR (CDCl₃) δ: 1.563 (s, 1H);1.772 (dd, J₁ =14 Hz, J₂ =3 Hz, 2H); 1.999 (quint, J=6 Hz, 2H); 2.137(td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.478 (td, J₁ =12 Hz, J₂ =2 Hz, 2H);2.575 (t, J=7 Hz, 2H); 2.811 (J₁ =11 Hz, J₂ =3 Hz, 2H); 3.803 (s, 3H);4.004 (t, J=6 Hz, 2H); 6.760 (dd, J.sub. 1 =9 Hz, J₂ =3 Hz, 1H); 6.887(d, J=9 Hz, 2H); 7.013 (d, J=3 Hz, 1H); 7.308 (d, J=9 Hz, 1H); 7.438 (d,J=9 Hz, 2H)

(2) To a stirred solution of 2.08 g of the compound (III-65) in 50 ml ofmethylene chloride is added 1.44 ml of BBr₃ under ice-cooling. Afterremoval of the reagent, the residue is poured into aq.NaHCO₃ andextracted with ethyl acetate. The organic layer is washed with water,dried and evaporated under reduced pressure. The resulting oily residue1.91 g is dissolved in 20 ml of CF₃ COOH and refluxed for 2 hour. Afterremoval of the reagent, the residue is poured into aq.NaHCO₃ andextracted with ethylacetate. The organic layer is washed, dried andevaporated. The residue is purified by column chromatography with silicagel, (toluene/ethyl acetate(1/1)-CH₂ Cl₂ /MeOH (20/1)) to prepare 270 mg(Yield: 33%) of the compound (I a-109) as a solid. The maleate isrecrystallized from MeOH-iPrOH to prepare needles. mp. 167.0°-168.0° C.(dec.)

Anal Calcd. (%) for C₂₀ H₂₁ NO₂ Cl₂ : C,58.08; H,5.05; N,2.93; Cl14.55Found: C, 58.31; H, 5.10; N, 2.83; Cl, 14.34

EXAMPLE 110

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridine(I a-110) ##STR82##

(1) 3-(3,4-dichlorophenoxy)propylchloride 1.38 g and4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in thesame manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl)piperidine(III-66). mp. 118.0°-118.5° C.

(2) A solution of 1.61 g of the compound (III-66) in 20 ml oftrifluoroacetic acid is refluxed for 3.5 hours. After removal of thereagent, the residue is poured into aq.NaHCO₃ and extracted withmethylene chloride. The organic layer is washed, dried and evaporated.The residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH(25/1) to prepare 1.45 g (Yield: 94.0%) of thecompound (I a-110) as oxalate. The oxalate is recrystallized fromMeOH-iPrOH to prepare the compound (I a-110) as needles. mp.163.5°-165.0° C. (dec.)

Anal Calcd. (%) for C₂₀ H₁₉ NO₂ Cl₄ : C, 50.43; H, 4.09; N, 2.72; Cl,27.15 Found: C, 50.70; H, 4.06; N, 2.69; Cl, 27.21 IR (Nujol): 2930,1713, 1695(sh), 1615, 1597, 1563 NMR (CDCl₃): 2.045 (quint, J=7 Hz, 2H);2.657 (t, J=8 Hz, 2H) 2.554 (m, 2H); 2.745 (t, J=5 Hz, 2H); 3.202 (q,J=3 Hz, 2H); 4.026 (t, J=6 Hz, 2H); 6.110 (m, 1H); 6.766 (dd, J₁ 19 Hz,J₂ 3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.19-7.47 (m, 4H)

EXAMPLE 111

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine(I a-111) ##STR83##

(1) 3-(3,4-dichlorophenoxy)propylchloride 2.00 g and4-hydroxy-4-(4-trifluoromethylphenyl)piperidine 1.95 g are reacted inthe same manner as Example 109 (1) to prepare 3.16 g (Yield: 88.7%) ofthe compound (III-67). mp. 196.0°-196.5° C.

(2) A solution of 2.65 g of the compound (III-67) in 30 ml oftrifluoroacetic acid is refluxed for 41 hours. After removal with thereagent, the residue is poured into aq.NaHCO₃ and extracted with ethylacetate. The organic layer is dried and evaporated. The residue ispurified by column chromatography of silica gel (toluene/ethyl acetate(3/1), CH₂ Cl₂ /MeOH(25/1)) to prepare 1.65 g (Yield: 65.9%) of thecompound (I a-111) as a solid, which is recrystallized from Et₂ O toprepare colorless needles, mp. 83.5°-84.0° C. The oxalate melts at mp.195.5°-196.0° C.

Anal Calcd. (%) for C₂₁ H₂₀ NO₂ Cl₂ F₃.C₂ H₂ O₄ : C, 52.93; H, 4.33; N,2.71; Cl, 13.42; F, 11.08 Found: C, 53.09; H, 4.26; N, 2.69; Cl, 13.65;F, 10.95 IR (CHCl₃): 2950, 2930, 2830, 2790, 1618, 1597, 1469 NMR(CDCl₃): 2.052 (quint, J=7 Hz, 2H); 2.52-2.65 (m, 2H); 2.661 (t, J=7 Hz,2H); 2.759 (t, J=6 Hz, 2H); 3.222 (q, J=3 Hz, 2H); 6.171 (m, 1H); 6.765(dd, J₁ =9 Hz, J₂ =3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.312 (d, J=9 Hz,1H); 7.479, 7.574 (ABq, J=8 Hz, 4H)

Reference Example 1

4-Hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1) ##STR84##

A mixture of 64.2 g of1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and asolution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours andevaporated. The reaction mixture is concentrated under reduced pressureand extracted with ethyl acetate. The organic layer is washed withwater, dried and evaporated. The resulting crystalline residue isrecrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0%) ofthe compound (E-1). mp. 144.5°-146.0° C.

Anal Calcd. (%) for C₁₄ H₁₇ NO₃ Cl₂ : C, 53.62; H, 5.26; N, 5.68; Cl,28.98 Found: C, 53.68; H, 5.32; N, 5.69; Cl, 28.81 IR (Nujol): 3320,3100, 1438 NMR (CD₃ OD) δ: 1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 1.936(td, J₁ =12 Hz, J₂ =5 Hz, 2H); 1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H);3.074 (td, J₁ =12 Hz, J₂ =3 Hz, 2H); 7.402 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H);7.480 (d, J=8 Hz, 1H); 7.662 (d, J=2 Hz, 1H)

Reference Example 2-19

The reaction is performed in the same manner as Reference Example 1 toprepare the compound (II). The reaction conditions and physicalconstants are shown in Tables 15 and 16.

                                      TABLE 15                                    __________________________________________________________________________     ##STR85##                                                                    Ref. (X)                             (II) g (Yield)                           Ex. No.                                                                            X =    Base    solvent                                                                              reflux time                                                                             m.p. (°C.)                        __________________________________________________________________________     2   CF.sub.3 (p)                                                                         KOH     EtOH   5    hours                                                                              (II-2)                                        27.3 g (28.07 g)                                                                             (450 ml)         13.24 g (63.0%)                               (X-2)                                                                     3   n-Pr (p)                                                                             KOH     n-BuOH 5.5  hours                                                                              (II-3)                                        44.0 g (49.3 g)                                                                              (640 ml)         30.47 g (92.0%)                               (X-3)                                                                     4   Et (p) KOH     n-BuOH 2    days (II-4)                                        22.42 g                                                                              (26.37 g)                                                                             (500 ml)         13.88 g (83.7%)                               (X-4)                                                                     5   Ph (p) KOH     n-BuOH 15   hours                                                                              (II-5)                                        18.65 g                                                                              (18.70 g)                                                                             (500 ml)         13.44 g (92.6%)                               (X-5)                                                                     6   t-Bu (p)                                                                             KOH     n-BuOH 5.5  hours                                                                              (II-6)                                        46.67 g                                                                              (50.9 g)                                                                              (700 ml)         33.64 g (92.0%)                               (X-6)                                                                    __________________________________________________________________________    Ref.  (X)                   (II) g (Yield)                                    Ex. No.                                                                            X =  Base solvent                                                                              reflux time                                                                         m.p. (°C.)                                                                     IR                                        __________________________________________________________________________     7   CH.sub.3 (p)                                                                       KOH  BuOH   3.5                                                                             hours                                                                             (II-8)  (Nujol)                                        49.86 g                                                                            (61.8 g)                                                                           (700 ml)     33.20 g (92.0%)                                                                       3310, 1598, 1502, 1490                         (X-7)                  135.5-137.5                                                                           1445                                       8   CH.sub.3 (m)                                                                       KOH  EtOH   6 days                                                                              (II-9)  (Nujol)                                        21.2 g                                                                             (26.3 g)                                                                           (450 ml)     10.25 g (66.6%)                                                                       3440, 3280, 3220, 3179                         (X-8)                  154.5-155.5                                                                           1606, 1590, 1490, 1475                     9   CH.sub.3 (o)                                                                       KOH  EtOH   5 days                                                                              (II-10) (Nujol)                                        14.7 g                                                                             (18.21 g)                                                                          (350 ml)     7.90 g (74.0%)                                                                        3440, 3280, 3220, 3170                         (X-9)                  141.0-142.0                                                                           1608, 1590, 1490                          10   3.4-diMe                                                                           KOH  EtOH   10                                                                              days                                                                              (II-11) (Nujol)                                        20.2 g                                                                             (23.76 g)                                                                          (500 ml)     13.97 g (93.5%)                                                                       3590, 3380, 1600, 1502                         (X-10)                 --      1467, 1448                                11   3.5-diMe                                                                           KOH  EtOH   12                                                                              days                                                                              (II-12) (Nujol)                                        22.7 g                                                                             (26.7 g)                                                                           (650 ml)     14.85 g (88.4%)                                                                       3280, 3120(br), 1605                           (X-11)                 182.0-183.0                                                                           1415                                      12   Cl (m)                                                                             KOH  EtOH   2 days                                                                              (II-13) (Nujol)                                        22.2 g                                                                             (25.5 g)                                                                           (350 ml)     13.68 g (82.6%)                                                                       3220, 3080, 1595, 1570                         (X-12)                 100.0-101.0                                                                           1432, 1408                                13   Cl (o)                                                                             NaOH THF/H.sub.2 O                                                                        5 days                                                                              (II-14) (KBr)                                          9.2 g                                                                              (3.89 g)                                                                           (10 ml/20 ml)                                                                              4.95 g (72.0%)                                                                        3440, 3280, 3060, 1475                         (X-13)                 166.5-167.5                                                                           1442, 1430                                14   3.5-diCl                                                                           KOH  EtOH   11                                                                              days                                                                              (II-15) (Nujol)                                        25.11 g                                                                            (25.74 g)                                                                          (550 ml)     15.5 g (79.8%)                                                                        3310, 3100, 3080, 1591                         (X-14)                 213.0-214.0                                                                           1568, 1450, 1425, 1410                    15   Br (p)                                                                             KOH  EtOH   10                                                                              days                                                                              (II-16) (Nujol)                                        21.0 g                                                                             (20.87 g)                                                                          (500 ml)     9.23 g (56.3%)                                                                        3280, 3050, 1588, 1492                         (X-15)                 159.5˜161.5                                                                     1478, 1420                                16   F (p)                                                                              KOH  Dioxane/H.sub.2 O                                                                    6 days                                                                              (II-17) (Nujol)                                        23.2 g                                                                             (17.36 g)                                                                          (170/70 ml)  9.82 g (58.8%)                                                                        3280, 3130, 1602, 1512                         (X-16)                 --      1455                                      17   CF.sub.3 (m)                                                                       KOH  nBuOH  2 hours                                                                             (II-18) (CHCl.sub.3)                                   Cl (p)                                                                             (42.7 g)                                                                           (580 ml)     22.30 g (67.0%)                                                                       3595, 2950, 2850, 1607                         41.8 g                 135.0-136.5                                                                           1576, 1483                                     (X-17)                                                                   18   *.sup.1                                                                            KOH  EtOH   2 days                                                                              (II-19) (Nujol)                                        (X-18)                                                                             (18.30 g)                                                                          (350 ml)     11.88 g 3290, 1540, 1417                               27.1 g                 149.5-150.0                                       19   *.sup.2                                                                            KOH  nBuOH  2 days                                                                              (II-20) (Nujol)                                        (X-19)                                                                             (19.82 g)                                                                          (500 ml)     9.51 g (62.1%)                                                                        3280, 1640, 1540                               19.7 g                 151.0-152.5                                       __________________________________________________________________________     ##STR86##                                                                     ##STR87##                                                                

                                      TABLE 16                                    __________________________________________________________________________    Cmpd.                                                                             m.p. (°C.)                                                                       Anal Calcd. (%)                                                 No. (solvent*)                                                                              Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                 __________________________________________________________________________    II-2                                                                              136.0-137.0                                                                             C.sub.12 H.sub.14 NOF.sub.3 :                                                           (Nujol) (CD.sub.3 OD)                                     (ethyl acetate)                                                                         C, 58.83 (58.77)                                                                        3290, 1619, 1443                                                                      1.680 (d-d, J.sub.1 = 14 Hz, J.sub.2 = 2                                      Hz, 2H); 2.004 (t-d, J.sub.1 = 14 Hz,                       H, 5.74 (5.75)                                                                          1439, 1422, 1410                                                                      J.sub.2 = 5 Hz, 2H); 2.866 (d-d, J.sub.1                                      = 13 Hz, J.sub.2 = 2 Hz, 2H); 3.107                         N, 5.73 (5.71)    (t-d, J.sub.1 = 13 Hz, J.sub.2 = 2 Hz,                                        2H);                                                        F, 23.13 (23.24)  7.625 (d, J = 9 Hz, 2H); 7.698 (d, J = 9                                      Hz, 2H)                                       II-3                                                                              178.5-179.5                                                                             C.sub.14 H.sub.21 NO.C.sub.2 H.sub.2 O.sub.4                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (oxalate) C, 61.77 (62.12)                                                                        3600, 3350(br),                                                                       0.933 (t, J = 7 Hz, 3H); 1.620 (sextet, J                                     =  8 Hz, 2H);                                     (i-PrOH)  H, 7.42 (7.49)                                                                          1593, 1510, 1468                                                                      1.876 (d, J = 14 Hz, 2H); 2.330 (t-d,                                         J.sub.1 = 14 Hz, J.sub.2 = 4 Hz, 2H);                       N, 4.50 (4.53)                                                                          1422    2.564 (t, J = 7 Hz, 2H); 3.244 (d, J = 12                                     Hz, 2H); 3.367 (t,                                                            J = 12 Hz, 2H); 7.164 (d, J = 8 Hz, 2H);                                      7.40 (d, J = 8 Hz, 2H)                        II-4                                                                              119.0-120.0                                                                             C.sub.13 H.sub.19 NO                                                                    (CHCl.sub.3)                                                                          (CD.sub.3 OD)                                     Et.sub.2 O-                                                                             C, 75.97 (76.05)                                                                        3600, 1510, 1469                                                                      1.204 (t, J = 7 Hz, 3H); 1.676 (d-d,                                          J.sub.1 = 14 Hz, J.sub.2 = 2 Hz, 2H);             ethyl acetate)                                                                          H, 9.33 (9.33)                                                                          1440, 1420, 1410                                                                      1.933 (t-d, J.sub.1 = 14 Hz, J.sub.2 = 5                                      Hz, 2H); 2.616 (q, J = 8 Hz, 2H);                           N, 6.78 (6.82)                                                                          (sh)    2.852 (d-d, J.sub.1 = 12 Hz, J.sub.2 = 3                                      Hz, 2H); 3.084 (t-d, J.sub.1 =  12 Hz,                                        J.sub.2 = 3 Hz, 2H); 7.156 (d, J = 8 Hz,                                      2H); 7.397 (d, J = 8 Hz, 2H)                  II-5                                                                              182.5-184.0                                                                             C.sub.17 H.sub.19 NO.                                                                   (Nujol) (CDCl.sub.3 --CD.sub.3 OD = 4/1)                  (MeOH--CH.sub.2 Cl.sub.2)                                                               1/6 H.sub.2 O                                                                           3320, 1595, 1581                                                                      1.804 (d, J = 12 Hz, 2H); 2.052 (t-d,                                         J.sub.1 = 14 Hz,                                            C, 79.84 (79.65)                                                                        1563, 1490, 1450                                                                      J.sub.2 = 5 Hz, 2H); 2.096 (d-d, J.sub.1                                      = 13 Hz, J.sub.2 = 2 Hz, 2H);                               H, 7.48 (7.60)    3.172 (t-d, J.sub.1 = 12 Hz, J.sub.2 = 3                                      Hz, 2H); 7.29-7.63 (m, 9H)                                  N, 5.44 (5.46)                                                  II-6                                                                              185.0-186.0                                                                             C.sub.15 H.sub.23 NO.H.sub.2 O                                                          (Nujol) (CD.sub.3 OD)                                     (CHCl.sub.3 --MeOH)                                                                     C, 71.18 (71.67)                                                                        3480(sh), 3390,                                                                       1.301 (s, 9H); 1.684 (d-d, J.sub.1 = 14                                       Hz, J.sub.2 = 2 Hz, 2H); 1.839                              H, 9.86 (10.02)                                                                         3320, 3290, 3090                                                                      (t-d, J.sub.1 = 14 Hz, J.sub.2 = 4 Hz,                                        2H); 2.857 (d-m, J.sub.1 = 12 Hz, 2H);                      N, 5.67 (5.57)                                                                          1668, 1508, 1470                                                                      3.086 (t-d, J.sub.1 = 13 Hz, J.sub.2 = 3                                      Hz, 2H); 7.360 (d, J = 9 Hz, 2H);                                             7.404 (d, J = 9 Hz)                           __________________________________________________________________________     *: a solvent for recrystallization                                       

Evaluation of Biological Activity

Experiment

After the decapitation of rats the objective tissues were rapidlyremoved and each was weighed. Each tissue was homogenized withtwenty-fold amount of ice-cold 50 mM Iris-HCl buffer (pH7.8)homogenized, and centrifuged at 40,000×g for 10 minutes. The supernatantwas removed and pellets were then resuspended in the buffer andrecentrifuged. The procedure is repeated 3 times. Then these obtainedsamples were freeze-dried in liquid nitrogen and preserved at -80° C. Onthe test day the sample was thawed at room temperature and centrifugedat 40,000×g for 10 minutes, the pellets were then suspended in anincubation buffer and used as the receptor preparation. The preparationwas added to the mixture containing the labelled ligand and the testdrug, and filtered through Whatman GF/C filters and washed to terminatethe reaction. Radioactivity on the filters was determined by a liquidscintillation counter and Ki value was calculated.

1. σ receptor

Sigma receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.7 mg protein/ml) to a mixture containing 5nM of [³ H]3PPP [3-hydroxyphenyl-N-(1-propyl)piperidine] and the testcompound dissolved in 50 mM Tris-HCl buffer (pH 7.8). Incubation wascarried out at 25° C. for 90 minutes. Specific sigma receptor bindingwas defined as the difference in amount of [³ H]3PPP bound to the tissuein the presence or the absence of 10 μM haloperidol.

2. DA2 receptor

DA2 receptor binding was initiated by the addition of the receptorpreparation (striatal tissue, 0.3 mg protein/ml) to a mixture containing0.2 nM of [³ H]spiroperidol and the test compound dissolved in 50 mMTris-HCl buffer containing 100 mM-NaCl and 5 mM-KCl (pH 7.4). Incubationwas carried out at 37° C. for 10 minutes. Specific DA2 receptor bindingwas defined as the difference in amount of [³ H]spiroperidol bound tothe tissue in the presence or the absence of 10 μM haloperidol.

3. 5HT2 receptor

5HT2 receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.5 mg protein/ml) to a mixture containing 1nM of [³ H]spiroperidol and the test compound dissolved in 50 mMTris-HCl buffer (pH 7.4). Incubation was carried out at 37° C. for 15minutes. Specific 5HT2 receptor binding was defined as the difference inamount of [³ H]spiroperidol bound to the tissue in the presence or theabsence of 1 mM serotonin.

4. PCP receptor

PCP receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.2 mg protein/ml) to a mixture containing 5nM of [³ H]TCP and the test compound dissolved in 5 mM Tris-HCl buffer(pH 7.8). Incubation was carried out at 25° C. for 30 minutes. SpecificPCP receptor binding was defined as the difference in amount of [³ H]TCPbound to the tissue in the presence or the absence of 10 μM PCP.

The test results are shown in Table 17.

                  TABLE 17                                                        ______________________________________                                        Test       Ki (μM)                                                         compound   PCP     σ    DA2    5-HT2                                    ______________________________________                                        I a-2      31      0.0041     4.7    0.55                                     I a-3      15      0.0095     4.0    1.70                                     I a-6      49      0.0027     2.2    2.50                                     I a-8      >62     0.0013     1.20   2.90                                     I a-9      33      0.0061     1.60   1.20                                     I a-11     23      0.0026     4.50   4.40                                     I a-13     26      0.0022     0.32   0.77                                     I a-24     32      0.0058     1.10   0.38                                     I a-30     >63     0.0013     2.00   3.70                                     I a-35     18      0.0018     4.60   3.20                                     I a-56     44      0.0065     4.50   8.90                                     I a-57     44      0.0063     2.40   0.14                                     I a-94     27      0.0013     1.40   1.90                                      I a-101   >63      0.00031   1.80   7.70                                      I a-102   >71      0.00071   3.20   5.70                                      I a-111   >63     0.0029     0.63   0.39                                      I a-112   >63     0.0025     >21    2.60                                     ______________________________________                                    

From the above, the compound of the present invention has low affinityto DA2 receptor and high affinity to σ receptor, and has useful activityas psychotropic agents.

What we claim is:
 1. A compound of the formula: ##STR88## wherein n isan integer of from 2 to 6; and p and q each is an integer of 0 or 1,excluding the case where p is 0 when q is 1;or a pharmaceuticallyacceptable acid addition salt thereof.